Management of Tacrolimus-Induced Toxicity With Normal Serum Levels After Liver Transplant.

Drug-induced liver injury after liver transplant occurs in 1.7% of patients. Tacrolimus is an effective immunosuppressant that is used to treat acute rejection. Although rare, it can cause toxicity, which is demonstrated by cholestatic liver injury. Here, we present a case of a young male patient who was diagnosed with Wilson disease, had penicillaminechelating therapy, and underwent living related liver transplant. Within 1 month posttransplant, he developed deranged, predominantly cholestatic pattern liver function tests. Laboratory parameters showed total bilirubin of 1.12 mg/ dL, alanine aminotransferase of 553 IU/L, gammaglutamyltransferase of 624 IU/L, and tacrolimus level of 10.2 ng/mL. After thorough evaluation, a liver biopsy was performed. Liver biopsy showed hepatocellular necrosis with centrilobular cholestasis without any evidence of graft rejection. However, with normal level of tacrolimus, the biopsy was suggestive of drug-induced liver injury. Thus, tacrolimus dose was reduced, resulting in improved liver function tests and patient discharge from the hospital. Tacrolimus is an effective immunosuppressant after liver transplant and has the ability to treat early acute rejection. The patient's liver biopsy showed hepatocellular necrosis with centrilobular cholestasis without any evidence of graft rejection. Cholestatic liver injury after tacrolimus usually resolves after dose reduction or by switching to another agent. With demonstrated tacrolimus-induced toxicity in liver transplant recipients, despite normal serum levels, transplant physicians should keep high index of suspicion regarding toxicity in the posttransplant setting.

Differential to Terminal Ileitis: Terminal Ileum Neuroendocrine Tumor Identified on Screening Colonoscopy.

Background: Asymptomatic patients at average risk of developing colorectal cancer are encouraged to undergo screening colonoscopy beginning at age 45 years. While ileal intubation is often considered the gold standard for a complete colonoscopy, the relatively low diagnostic yield has prevented widespread adoption. Small bowel cancers, including neuroendocrine tumors, may present incidentally as terminal ileitis on routine colonoscopy with terminal ileum intubation. Neuroendocrine tumors, the most common primary neoplasm of the small intestine, are often asymptomatic or present as nonspecific abdominal pain in the sixth or seventh decade of life. Case Report: A 51-year-old asymptomatic male with unremarkable physical examination underwent screening colonoscopy that revealed scattered ulcerations of the terminal ileum. Immunohistochemistry of the lesion was consistent with well-differentiated neuroendocrine tumor, World Health Organization Grade I. DOTATATE positron emission tomography/computed tomography demonstrated avid adjacent right mesenteric lymph node and avid focal pancreatic body lesion. Fine-needle biopsy and immunohistochemistry of the pancreatic lesion confirmed neuroendocrine tumor, while the mesenteric lymph node was found to be benign. The patient underwent robotic-assisted ileocolic resection and has ongoing surveillance of the pancreatic lesion. Conclusion: Terminal ileitis encompasses a host of pathologic processes, including inflammatory states, infectious disease, malignancy, and vasculitis. Importantly, small bowel cancer is an increasing cause of terminal ileitis. Screening colonoscopy with ileal intubation can be a valuable tool for early detection of these lesions.

Rosai Dorfman Disease With Extensive Bony Involvement- A Diagnostic Dilemma.

Previously classified as Non Langerhan cell histiocytosis by the Working Group of Histiocytic Society in 1987 Rosai Dorfman Destombes disease was first described by Destombes in 1965 and later in 1969 by Rosai and Dorfman as a rare histiocytic disorder with sinus histiocytosis and massive lymphadenopathy. They exist in both nodal and extranodal forms. Immunohistochemistry is an essential part of diagnosis to differentiate between Langerhans cell histiocytosis and another malignant histiocytosis. Some overlap has also been reported with IgG4-related diseases. We hereby reflect upon a patient who presented to our facility with pyrexia of unknown origin, the challenges faced to reach a diagnosis and the management offered.

Pancreatic Tuberculosis mimicking as a Pancreatic Mass Lesion.

Tuberculosis is a global health problem and commonly affects the respiratory system. The involvement of the pancreas in this disease is a rare event. We hereby report a case of a young male who presented with right hypochondrial pain along with significant weight loss. Further workup revealed a raised erythrocyte sedimentation rate along with a pancreatic mass lesion on the CT scan. Endoscopic ultrasound-guided biopsy of the pancreatic lesion revealed evidence of caseation necrosis along with epithelioid granuloma, findings suggestive of tuberculosis. He was started on anti-tuberculous therapy for 6 months and a repeat CT scan showed complete disappearance of the mass lesion and resolution of symptoms. Key Words: Tuberculosis, Pancreatic mass, Endoscopic ultrasound, Biopsy.

Age-Dependent Effects of Copper Toxicity on Connective Tissue Structural Stability in Wistar Rats Skin.

Over the last three decades, there has been increasing global concern over the public health impacts attributed to direct and indirect environmental pollution, in particular, the global burden of disease. The World Health Organization estimates that, about a quarter of the diseases facing mankind today occur due to prolonged exposure to environmental pollution; the health of 200 million people in lower-income countries is at risk from toxins such as lead and copper or mercury, more than from AIDS, tuberculosis and malaria combined and that, nearly a quarter of deaths in developing countries including Nigeria and Ghana, are linked to pollution. The purpose of the study was to investigate the effects of the ingestion of large dose of copper on the structural stability of collagen molecules, as well as reveal age-dependent differences in the phenomena.  The content of de novo synthesized collagen was determined by hydroxyproline concentration using Stegmann-Staeder's method as modified by Utevskaya and Persky; the nature of intra- and inter-molecular covalent cross-links in collagen matrix was estimated by electrophoretic separation of products of partial thermal denaturation of collagen in polyacrylamide gel. There was intensification of synthesis over degradation in young rats, and that administration of copper led to a decrease in collagen solubility. Effects of copper on the structural stability of collagen appeared mostly in young rats.

Kratom (Mitragyna speciosa)-Induced Hepatitis.

Kratom is a plant with opioid-like properties known to produce stimulant and analgesic effects. Although there are numerous studies on the psychoactive components of kratom, less is known about the toxicity. Specifically, few reports describe kratom-induced hepatotoxicity and demonstrate histological features. We provide a case report detailing the clinicopathologic findings of drug-induced liver injury caused by kratom. The laboratory workup included significant elevation of total bilirubin and alkaline phosphatase. Liver biopsy demonstrated a prominent canalicular cholestatic pattern, mixed portal inflammation, and newly described perivenular necrosis. This report provides additional information on kratom toxicity because its use continues to rise.

Knowledge, attitudes and practices towards deceased organ donation among parents of children with End Stage Kidney Disease.

OBJECTIVE: To assess the knowledge, attitudes, and practices (KAP) towards deceased organ donation (DOD) of the parents/ guardians of children with end stage kidney disease (ESKD). METHODS: This cross sectional survey was conducted between April and December 2020. A structured questionnaire was filled to assess the sociodemographic information, knowledge, attitude, and practice about DOD. RESULTS: A total of 130 participants with a mean age of 37±7 years were included in the study. Among all, 66 (50.8%) claimed that they had prior knowledge about DOD. However, on further questioning, no one knew who can be the deceased organ donor. Their responses about registration place and permission from religion were positive in 24(36.4%) and 31(47.0%) cases respectively. Regarding attitude, positive responses to willingness to get registered and discussing DOD in social circle were given by 37(56.1%) and 21 (31.8%) participants respectively. Only one participant was registered as donor. The remaining 64(49.2%) participants who had no prior knowledge were given relevant information and were interviewed after one week. Only 24(37.5%) showed willingness to get registered as donors and 06 (9.4%) participants discussed the topic of DOD in their social circle. CONCLUSIONS: The results showed that the knowledge, attitudes, and practices of people who are most desperate for transplantation of their children were poor and did not change significantly even after providing them relevant information.

Mineral biofortification of vegetables through soil-applied poultry mortality compost.

Intensive agricultural practices lower soil fertility, particularly micronutrients which are rarely applied to soils as chemical fertilizers. Micronutrient deficiency in soils results in inferior product quality and micronutrient malnutrition in humans. Application of compost to soil may improve crop yields and quality by enhancing macro- and micronutrients availability, enhancing soil microbial population, and improving soil physicochemical properties. Poultry mortality compost (PMC) was prepared by decomposing dead poultry birds with poultry litter in an aerated bin through indigenous microbial populations. The prepared PMC was used as an amendment in three field experiments during 2017-18 and 2018-19 to investigate the effect on yield and nutritional quality of potato, carrot, and radish. In these field trials, two compost levels, i.e., 1250 kg ha-1 (PMC1) and 1850 kg ha-1 (PMC2) were compared with the control (no compost application). The results revealed a 10-25% increase in root or tuber yield at PMC2 compared to that in the control. A substantial increase in Zn, Fe, and Mn concentrations in vegetable root/tubers was also observed. Organic matter content and microbial biomass were improved in the soil with PMC application leading to better soil health and better nutrient availability. These studies led us to conclude that the application of PMC not only enhances the vegetable yield but also biofortifies vegetables with micronutrients such as Zn, Fe, and Mn extending agricultural sustainability and eliminating micronutrient malnutrition in humans.

Intestinal Spirochaetosis-A case series from the developing world.

Spirochaetes comprise a heterogenous group of gram negative, motile, spiral shaped bacteria. Some of these pathogens are known to cause numerous human diseases such as Lyme disease, relapsing fever, syphilis and leptospirosis. However, intestinal spirochetosis is a rare condition. Patients frequently present with long-term complaints of loose stools, abdominal pain and weight loss and rectal bleeding. Hence to establish a diagnosis an endoscopy with biopsy is required. In this article, we describe four such cases, having different ages and socio- economic background, successfully treated with a short course of metronidazole.

Human papillomavirus-associated anal squamous intraepithelial lesions in men who have sex with men and transgender women living with and without HIV in Karachi Pakistan: implications for screening and prevention.

BACKGROUND: Anal squamous intraepithelial lesions (ASIL), strongly related to human papilloma virus (HPV) infection, is more prevalent among men who have sex with men (MSM). However, no such data are available for Pakistan yet, and neither HPV vaccination nor anal-cytology screening is implemented in Pakistan. The purpose of this first ever study was to assess the prevalence of HPV-related anal cytological abnormalities among MSM and transgender women living with and without HIV infection in Pakistan. METHODS: We conducted a cross-sectional study from March 2016 to November 2017 at sexual health centers run by the Perwaaz Trust and the National AIDS Control Program in Karachi. The study enrolled MSM and transgender women aged greater-than-and-equal-to-18-years who reported anal sex in the preceding 6 months. We collected two anal samples for liquid-based cytology and HPV type testing by PCR, and socio-demographic and behavioral data were collected through face-to face interviews. ASIL and its associations with biological and behavioral risk factors were analyzed through Cox regression for prevalence ratios (PR) and corresponding 95% confidence intervals (CIs). RESULTS: Out of 271 qualifying participants, 79% were MSM and 21% transgender women. The mean age was 28.8 (± 8) years. Almost 35% (93/271) of the study population had ASIL detected, ASIL was significantly more common among participants living with HIV than in HIV negative ((50/118) 42.4%; vs. (43/153) 28.1%) (p ≤ 0.001). Among ASIL, 66% (61/93) had low-grade squamous intraepithelial lesions (LSIL), and 3.6% (3/93) had high-grade squamous intraepithelial lesions (HSIL). The overall, HPV16 positivity was 35.5% (33/93) among all abnormal anal lesions and all 3 HSIL were HPV16 positive, however, HPV16 positivity could show its association with ASIL detection in univariate model only (PRcrude: 2.11(1.39-3.18)). Moreover, any HR-HPV type (PR 3.04; 95% CI 1.75-5.26), concurrent sexually transmitted infection (STI) (2.13; (1.28-3.55)) and HIV + /HPV + coinfection (1.75; (1.07-2.88)) remained independently associated with ASIL in the multivariate model. CONCLUSIONS: Abnormal anal cytology among MSM and transgender is prevalent enough to consider optimal screening regimens. Further studies are required to see if periodic anal cytology can be made part of HIV care and treatment programs among MSM in Pakistan.

Brain Abscesses in Crohn's Disease as a Complication of Infliximab Therapy.

Infliximab therapy is highly effective in the treatment of Crohn's disease. Infliximab-induced immunosuppression increases the risk for various infections, including opportunistic infections. We describe a case of brain abscesses as a complication of infliximab therapy in a 65-year-old man. It was elucidated that the brain abscesses developed from the presumed hematogenous spread of bacteria from recently treated paraspinal abscesses. Close attention should be given to patients on infliximab therapy presenting with any neurological sign or symptom to allow for timely diagnosis and prompt management of a potential central nervous system infection.

Hydroxyl Transfer to Carbon Radicals by Mn(OH) vs Fe(OH) Corrole Complexes.

The transfer of •OH from metal-hydroxo species to carbon radicals (R•) to give hydroxylated products (ROH) is a fundamental process in metal-mediated heme and nonheme C-H bond oxidations. This step, often referred to as the hydroxyl "rebound" step, is typically very fast, making direct study of this process challenging if not impossible. In this report, we describe the reactions of the synthetic models M(OH)(ttppc) (M = Fe (1), Mn (3); ttppc = 5,10,15-tris(2,4,6-triphenyl)phenyl corrolato3-) with a series of triphenylmethyl carbon radical (R•) derivatives ((4-X-C6H4)3C•; X = OMe, tBu, Ph, Cl, CN) to give the one-electron reduced MIII(ttppc) complexes and ROH products. Rate constants for 3 for the different radicals ranged from 11.4(1) to 58.4(2) M-1 s-1, as compared to those for 1, which fall between 0.74(2) and 357(4) M-1 s-1. Linear correlations for Hammett and Marcus plots for both Mn and Fe were observed, and the small magnitudes of the slopes for both correlations imply a concerted •OH transfer reaction for both metals. Eyring analyses of reactions for 1 and 3 with (4-X-C6H4)3C• (X = tBu, CN) also give good linear correlations, and a comparison of the resulting activation parameters highlight the importance of entropy in these •OH transfer reactions. Density functional theory calculations of the reaction profiles show a concerted process with one transition state for all radicals investigated and help to explain the electronic features of the OH rebound process.

Online hemodiafilteration use in children: a single center experience with a twist.

BACKGROUND: Haemodiafilteration (HDF) is a promising new modality of renal replacement therapy (RRT). It is an improvement in the quality of hemodialysis (HD) and thus in the quality of patients'lives. The main obstacle to using HDF is the cost, especially in developing countries. The purpose of this study was to evaluate the benefits of incorporating HDF with different regimens in the treatment of children with end stage renal disease (ESRD). METHODS: Thirty-four children with ESRD on regular HD in Pediatric Dialysis Unit, Children's Hospital, Ain Shams University were followed up in 2 phases: initial phase (all patients: HD thrice weekly for 3 months) and second phase, patients were randomized into 2 groups, HDF group and HD group, the former was subdivided into once and twice weekly HDF subgroups. Evaluation using history, clinical and laboratory parameters at 0, 3, 9 and 18 months was carried out. RESULTS: On short term, we found that the HDF group was significantly superior to HD group regarding all clinical and laboratory parameters. Also, twice HDF subgroup was significantly superior to once HDF subgroup. This was confirmed on long term follow up, but the once HDF proved comparable to twice subgroup. CONCLUSIONS: Incorporating online hemodiafilteration (OL-HDF) in the RRT of children was beneficial in most of the clinical and laboratory parameters measured. It's not all or non; OL-HDF, even once a week, can improve outcomes of HD without significantly affecting the cost.

Helicobacter pylori severely reduces expression of DNA repair proteins PMS2 and ERCC1 in gastritis and gastric cancer.

Gastric cancers are the third leading cause of cancer mortality in the world. Helicobacter pylori causes over 60 % of all stomach cancers. Colonization of the gastric mucosa by H. pylori results in increased DNA damage. Repair of DNA damage may also be reduced by H. pylori infection. Reduced DNA repair in combination with increased DNA damage can cause carcinogenic mutations. During progression to gastric cancer, gastric epithelium goes through stages of increasing pathology. Determining the levels of DNA repair enzymes during progression to gastric cancer could illuminate treatment approaches. Our aim is to determine the level of gastric expression of DNA repair proteins ERCC1 (a nucleotide excision repair enzyme) and PMS2 (a mismatch repair enzyme) in the presence of H. pylori infection at successive stages of gastric pathology and in gastric cancers. We analyzed gastric tissues of 300 individuals, including 30 without dyspepsia, 200 with dyspepsia and 70 with gastric cancers. The presence of H. pylori, gastric pathology and expression of DNA repair proteins ERCC1 and PMS2 were evaluated. Infection by H. pylori carrying the common cagA gene reduced median nuclear expression of ERCC1 and PMS2 to less than 20 % and 15 % of normal, respectively, in all pathologic stages preceding cancer. ERCC1 and PMS2 nuclear expression was 0-5 % of normal in gastric cancers. H. pylori can cause deficiency of ERCC1 and PMS2 protein expression. These deficiencies are associated with gastric pathology and cancer. This reduction in DNA repair likely causes carcinogenic mutations. Substantially reduced ERCC1 and PMS2 expression appears to be an early step in progression to H. pylori-induced gastric cancer.

Frequencies of Common Infectious Organisms Causing Chronic Diarrhea in Renal Transplant Patients.

OBJECTIVES: Gastrointestinal complications are common in kidney transplant patients, with the most frequent being diarrhea (60%). Chronic diarrhea affects the patient's quality of life, causes fatigue and weight loss and malabsorption, increases the number of hospitalizations, increases serum creatinine levels, and causes alterations in immunosuppressive drug levels. Diarrhea is also associated with an increased risk of graft failure and death. In this study, we aimed to determine the frequencies of common infectious organisms causing chronic diarrhea in renal transplant patients. MATERIALS AND METHODS: Our study included 124 renal transplant patients who presented with chronic diarrhea over a 6-month period at the Sindh Institute of Urology and Transplantation Department tertiary care hospital (Karachi, Pakistan). Stool analysis was performed in all transplant recipients. Upper and lower gastrointestinal endoscopy was also performed in patients with chronic diarrhea, and biopsy specimens underwent histopathologic evaluations. RESULTS: Of 124 renal transplant recipients, 29 were female (23.4%) and 95 were male (76.6%). Giardia was the most common organism found (n = 37 patients; 29.8%) followed by Cryptosporidium (n = 36; 29.0%), Entameba histolytica (n = 29; 23.4%), tuberculosis (n = 14; 11.3%), and sprue (n =8; 6.5%). The mean duration since renal transplant was 78.5 ± 63.37 months. Although not statistically significant, the frequency of diarrhea was higher in patients who had transplant procedures ≥ 2 years previously. CONCLUSIONS: Chronic diarrhea is prevalent in renal transplant patients irrespective of age, sex, and duration since transplant. Giardiasis and Cryptosporidium species infections are important causes of chronic diarrhea, but other causative factors need to be further studied, including comorbid conditions and immunosuppressive agents.

Metastatic Renal Cell Carcinoma Presenting as a Bleeding Gastric Polyp.

BACKGROUND: Renal cell carcinoma (RCC) is responsible for nearly 13,000 deaths in the United States every year, predominantly because of metastasis to other bodily organs. However, metastasis of RCC to the stomach occurs rarely; it presents as solitary or multiple polyps or as ulcers concerning for primary gastric carcinoma. Bleeding from metastasis to the stomach is a rare and underrecognized cause of gastrointestinal bleeding. We describe a case of gastrointestinal bleeding in an elderly female who was found to have a gastric polyp of RCC origin. CASE REPORT: An 83-year-old female presented to our hospital for evaluation of an acute right basal ganglia hemorrhage after falling at her nursing home. Her hospital course was notable for melenic stool and anemia. Upper endoscopy revealed a single 40-mm pedunculated polyp and active bleeding on the lesser curvature of the stomach. Polypectomy and clipping were performed. Pathology was consistent with metastatic clear cell RCC. The patient's family declined a referral to oncology for evaluation of the newly diagnosed malignancy and opted for hospice care. CONCLUSION: This case illustrates the potential for metastatic RCC to involve the stomach and cause gastrointestinal bleeding and anemia. The case also illustrates the role of upper gastrointestinal endoscopy in diagnosing and treating metastatic causes of gastrointestinal bleeding.

Diagnostic Accuracy of Aspartate Aminotransferase to Platelet Ratio Index and Fibrosis 4 Scores in Predicting Advanced Liver Fibrosis in Patients with End-stage Renal Disease and Chronic Viral Hepatitis: Experience from Pakistan.

OBJECTIVES: The aim was to assess the diagnostic accuracy of APRI and FIB-4 in assessing the stage of liver fibrosis in end stage renal disease (ESRD) patients with chronic viral hepatitis and to compare the two tests with standard tru-cut liver biopsy. MATERIAL AND METHODS: The study was conducted at Sindh Institute of Urology and Transplantation Karachi (SIUT) from May 2010 to May 2014. All ESRD patients, being considered as candidates for renal transplantation and in whom liver biopsy was performed were included. Fibrosis stage was assessed on liver biopsy using Ishak scoring system. The serum transaminases and platelet counts were used to calculate APRI and FIB-4 scores. RESULTS: Out of 109 patients, hepatitis C and B virus infections were present in 104 (95.4%) and 3(2.8%), respectively, while 2 (1.8%) patients had both infections. The mean Ishak fibrosis score was 1.95 ± 2. Advanced fibrosis was noted in 37 (34%) patients. Univariate analysis showed that advanced liver fibrosis was associated with lower platelets counts (P=0.001) and higher aspartate aminotransferase (AST) (P=0.001), alanine aminotransferase (ALT) (P=0.022), APRI score (P=0.001) and FIB-4 score (P=0.001). On logistic regression analysis, only APRI score (P < 0.001) was found to be the independent variable associated with advanced liver fibrosis. APRI score cutoff ≥1 indicating advanced fibrosis showed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 91.9%, 90.3%, 82.9%, 95.6%, respectively with area under the curve (AUC) of 0.97. Similarly, a FIB-4 score cutoff ≥1.1 had sensitivity, specificity, PPV and NPV of 70.27%, 66.67%, 52% and 81.36%, respectively with AUC of 0.74. CONCLUSION: APRI is more accurate noninvasive test for assessing advanced liver fibrosis in ESRD patients as compared to FIB-4. It can be used to obviate the need for liver biopsy in this high risk population.

α7-nAChR Knockout Mice Decreases Biliary Hyperplasia and Liver Fibrosis in Cholestatic Bile Duct-Ligated Mice.

α7-nAChR is a nicotinic acetylcholine receptor [specifically expressed on hepatic stellate cells (HSCs), Kupffer cells, and cholangiocytes] that regulates inflammation and apoptosis in the liver. Thus, targeting α7-nAChR may be therapeutic in biliary diseases. Bile duct ligation (BDL) was performed on wild-type (WT) and α7-nAChR-/- mice. We first evaluated the expression of α7-nAChR by immunohistochemistry (IHC) in liver sections. IHC was also performed to assess intrahepatic bile duct mass (IBDM), and Sirius Red staining was performed to quantify the amount of collagen deposition. Immunofluorescence was performed to assess colocalization of α7-nAChR with bile ducts (costained with CK-19) and HSCs (costained with desmin). The mRNA expression of α7-nAChR, Ki-67/PCNA (proliferation), fibrosis genes (TGF-ß1, fibronectin-1, Col1α1, and α-SMA), and inflammatory markers (IL-6, IL-1ß, and TNF-α) was measured by real-time PCR. Biliary TGF-ß1 and hepatic CD68 (Kupffer cell marker) expression was assessed using IHC. α7-nAChR immunoreactivity was observed in both bile ducts and HSCs and increased following BDL. α7-nAChR-/- BDL mice exhibited decreased (i) bile duct mass, liver fibrosis, and inflammation, and (ii) immunoreactivity of TGF-ß1 as well as expression of fibrosis genes compared to WT BDL mice. α7-nAChR activation triggers biliary proliferation and liver fibrosis and may be a therapeutic target in managing extrahepatic biliary obstruction.