Fetal liver CD34+ contain human immune and endothelial progenitors and mediate solid tumor rejection in NOG mice.

BACKGROUND: Transplantation of CD34+ hematopoietic stem and progenitor cells (HSPC) into immunodeficient mice is an established method to generate humanized mice harbouring a human immune system. Different sources and methods for CD34+ isolation have been employed by various research groups, resulting in customized models that are difficult to compare. A more detailed characterization of CD34+ isolates is needed for a better understanding of engraftable hematopoietic and potentially non-hematopoietic cells. Here we have performed a direct comparison of CD34+ isolated from cord blood (CB-CD34+) or fetal liver (FL-CD34+ and FL-CD34+CD14-) and their engraftment into immunocompromised NOD/Shi-scid Il2rgnull (NOG) mice. METHODS: NOG mice were transplanted with either CB-CD34+, FL-CD34+ or FL-CD34+CD14- to generate CB-NOG, FL-NOG and FL-CD14--NOG, respectively. After 15-20 weeks, the mice were sacrificed and human immune cell reconstitution was assessed in blood and several organs. Liver sections were pathologically assessed upon Haematoxylin and Eosin staining. To assess the capability of allogenic tumor rejection in CB- vs. FL-reconstituted mice, animals were subcutaneously engrafted with an HLA-mismatched melanoma cell line. Tumor growth was assessed by calliper measurements and a Luminex-based assay was used to compare the cytokine/chemokine profiles. RESULTS: We show that CB-CD34+ are a uniform population of HSPC that reconstitute NOG mice more rapidly than FL-CD34+ due to faster B cell development. However, upon long-term engraftment, FL-NOG display increased numbers of neutrophils, dendritic cells and macrophages in multiple tissues. In addition to HSPC, FL-CD34+ isolates contain non-hematopoietic CD14+ endothelial cells that enhance the engraftment of the human immune system in FL-NOG mice. We demonstrate that these CD14+CD34+ cells are capable of reconstituting Factor VIII-producing liver sinusoidal endothelial cells (LSEC) in FL-NOG. However, CD14+CD34+ also contribute to hepatic sinusoidal dilatation and immune cell infiltration, which may culminate in a graft-versus-host disease (GVHD) pathology upon long-term engraftment. Finally, using an HLA-A mismatched CDX melanoma model, we show that FL-NOG, but not CB-NOG, can mount a graft-versus-tumor (GVT) response resulting in tumor rejection. CONCLUSION: Our results highlight important phenotypical and functional differences between CB- and FL-NOG and reveal FL-NOG as a potential model to study hepatic sinusoidal dilatation and mechanisms of GVT.

Identification of small molecules targeting homoserine acetyl transferase from Mycobacterium tuberculosis and Staphylococcus aureus.

There is an urgent need to validate new drug targets and identify small molecules that possess activity against both drug-resistant and drug-sensitive bacteria. The enzymes belonging to amino acid biosynthesis have been shown to be essential for growth in vitro, in vivo and have not been exploited much for the development of anti-tubercular agents. Here, we have identified small molecule inhibitors targeting homoserine acetyl transferase (HSAT, MetX, Rv3341) from M. tuberculosis. MetX catalyses the first committed step in L-methionine and S-adenosyl methionine biosynthesis resulting in the formation of O-acetyl-homoserine. Using CRISPRi approach, we demonstrate that conditional repression of metX resulted in inhibition of M. tuberculosis growth in vitro. We have determined steady state kinetic parameters for the acetylation of L-homoserine by Rv3341. We show that the recombinant enzyme followed Michaelis-Menten kinetics and utilizes both acetyl-CoA and propionyl-CoA as acyl-donors. High-throughput screening of a 2443 compound library resulted in identification of small molecule inhibitors against MetX enzyme from M. tuberculosis. The identified lead compounds inhibited Rv3341 enzymatic activity in a dose dependent manner and were also active against HSAT homolog from S. aureus. Molecular docking of the identified primary hits predicted residues that are essential for their binding in HSAT homologs from M. tuberculosis and S. aureus. ThermoFluor assay demonstrated direct binding of the identified primary hits with HSAT proteins. Few of the identified small molecules were able to inhibit growth of M. tuberculosis and S. aureus in liquid cultures. Taken together, our findings validated HSAT as an attractive target for development of new broad-spectrum anti-bacterial agents that should be effective against drug-resistant bacteria.

Gut-Evolved Candida albicans Induces Metabolic Changes in Neutrophils.

Serial passaging of the human fungal pathogen Candida albicans in the gastrointestinal tract of antibiotics-treated mice selects for virulence-attenuated strains. These gut-evolved strains protect the host from infection by a wide range of pathogens via trained immunity. Here, we further investigated the molecular and cellular mechanisms underlying this innate immune memory. Both Dectin-1 (the main receptor for ß-glucan; a well-described immune training molecule in the fungal cell wall) and Nod2 (a receptor described to mediate BCG-induced trained immunity), were redundant for the protection induced by gut-evolved C. albicans against a virulent C. albicans strain, suggesting that gut-evolved C. albicans strains induce trained immunity via other pathways. Cytometry by time of flight (CyTOF) analysis of mouse splenocytes revealed that immunization with gut-evolved C. albicans resulted in an expansion of neutrophils and a reduction in natural killer (NK) cells, but no significant numeric changes in monocytes, macrophages or dendritic cell populations. Systemic depletion of phagocytes or neutrophils, but not of macrophages or NK cells, reduced protection mediated by gut-evolved C. albicans. Splenocytes and bone marrow cells of mice immunized with gut-evolved C. albicans demonstrated metabolic changes. In particular, splenic neutrophils displayed significantly elevated glycolytic and respiratory activity in comparison to those from mock-immunized mice. Although further investigation is required for fully deciphering the trained immunity mechanism induced by gut-evolved C. albicans strains, this data is consistent with the existence of several mechanisms of trained immunity, triggered by different training stimuli and involving different immune molecules and cell types.

Sirtuin 3 Downregulation in Mycobacterium tuberculosis-Infected Macrophages Reprograms Mitochondrial Metabolism and Promotes Cell Death.

Mycobacterium tuberculosis induces metabolic reprogramming in macrophages like the Warburg effect. This enhances antimicrobial performance at the expense of increased inflammation, which may promote a pathogen-permissive host environment. Since the NAD+-dependent protein deacetylase Sirtuin 3 (SIRT3) is an important regulator of mitochondrial metabolism and cellular redox homeostasis, we hypothesized that SIRT3 modulation mediates M. tuberculosis-induced metabolic reprogramming. Infection of immortalized and primary murine macrophages resulted in reduced levels of SIRT3 mRNA and protein and perturbation of SIRT3-regulated enzymes in the tricarboxylic acid cycle, electron transport chain, and glycolytic pathway. These changes were associated with increased reactive oxygen species and reduced antioxidant scavenging, thereby triggering mitochondrial stress and macrophage cell death. Relevance to tuberculosis disease in vivo was indicated by greater bacterial burden and immune pathology in M. tuberculosis-infected Sirt3-/- mice. CD11b+ lung leukocytes isolated from infected Sirt3-/- mice showed decreased levels of enzymes involved in central mitochondrial metabolic pathways, along with increased reactive oxygen species. Bacterial burden was also greater in lungs of LysMcreSirt3L2/L2 mice, demonstrating the importance of macrophage-specific SIRT3 after infection. These results support the model of SIRT3 as a major upstream regulatory factor, leading to metabolic reprogramming in macrophages by M. tuberculosisIMPORTANCE Tuberculosis, the disease caused by the bacterium M. tuberculosis, remains one of the top 10 causes of death worldwide. Macrophages, the first cells to encounter M. tuberculosis and critical for defense against infection, are hijacked by M. tuberculosis as a protected growth niche. M. tuberculosis-infected macrophages undergo metabolic reprogramming where key mitochondrial pathways are modulated, but the mechanisms driving this metabolic shift is unknown. Our study demonstrates that M. tuberculosis downregulates Sirtuin 3 (SIRT3), an important regulator of mitochondrial metabolism, leading to SIRT3-dependent transcriptional downregulation of mitochondrial metabolic proteins, which is followed by oxidative stress and macrophage necrosis. This study identifies SIRT3 modulation as a key event in M. tuberculosis-induced metabolic reprograming in macrophages that defend against tuberculosis.

Convalescent plasma therapy and remdesivir duo successfully salvaged an early liver transplant recipient with severe COVID-19 pneumonia.

The impact and clinical spectrum of COVID-19 infection in liver transplant recipients/solid organ transplants are being unveiled during this recent pandemic. The clinical experience of use of current antiviral drugs and immunomodulators are sparse in solid organ transplantation. We present the clinical course of a 49-year-old male recipient who underwent living donor liver transplant for recurrent gastrointestinal bleed and contracted severe COVID-19 pneumonia during the third postoperative week. Herein we report the successful management of severe COVID-19 pneumonia using convalescent plasma therapy and remdesivir. Recipient's clinical deterioration was halted after three consecutive convalescent plasma transfusions with improvement in hypoxia and inflammatory markers (interleukin-6 and C-reactive protein). The use of convalescent plasma therapy along with remdesivir may be an ideal combination in the management of severe COVID-19 pneumonia in solid organ transplant recipients.

Effectiveness of Nasal Packing in Trans-septal Suturing Technique in Septoplasty: A Randomized Comparative Study.

Nasal packing is routinely used after septoplasty, but there are patient factors for which its use needs to be reconsidered. Effectiveness of nasal packing in trans-septal suturing technique in septoplasty. Prospective, comparative study, patients submitted to septoplasty were randomized to receive or not nasal packing postoperatively. Comparison in postoperative status for pain, headache, discomfort in swallowing, epiphora, bleeding, infection and pain on pack removal are assessed. In all the patients trans-septal suturing technique was used. Study group has 60 patients. Two groups were made group A in whom nasal packing done post operatively with merocel, group B in whom nasal packing was not done, in both groups quilting sutures were applied on to the septum. There was pain in nose and headache in all the patients in group A. Other symptoms in group A were epiphora, discomfort in swallowing due to ear discomfort. In addition to these there is pain on removal of packs. Routine use of nasal packing can be avoided instead sutures can be placed over the septum, which benefits in improving pain and symptoms due to pack in the postoperative period.

Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation.

Resistin is a key cytokine associated with metabolic and inflammatory diseases. Especially in East Asian populations, the expression levels are strongly influenced by genetic polymorphisms. Mechanisms and functional implications of this genetic control are still unknown. By employing reporter assays, EMSA, inhibition studies, bisulphite sequencing, ChIP-Seq and gene-editing we show that the p50/p50 homodimer known to act as repressor for a number of pro-inflammatory genes plays a central role in the genetic regulation of resistin in monocytes along with promoter methylation. In the common RETN haplotype p50/p50 constitutively dampens the expression by binding to the promoter. In an Asian haplotype variant however this interaction is disrupted by the A allele of rs3219175. The SNP is in very close linkage to rs34861192, a CpG SNP, located 280 bp upstream which provides an allele-specific C-methylation site. rs34861192 is located in a 100 bp region found to be methylated in the common but not in the Asian haplotype, resulting in the latter having a higher basal expression, which also associates with elevated histone acetylation (H3K27ac). Genotype associations within cohort data of 200 East Asian individuals revealed significant associations between this haplotype and the plasma levels of factors such as TGF-b, S100B, sRAGE and IL-8 as well as with myeloid DC counts. Thus, the common RETN haplotype is tightly regulated by the epigenetic mechanism linked to p50/p50-binding. This control is lost in the Asian haplotype, which may have evolved to balance the antagonistic RETN effects on pathogen protection vs. metabolic and inflammatory disease induction.

mTORC2/Akt activation in adipocytes is required for adipose tissue inflammation in tuberculosis.

BACKGROUND: Mycobacterium tuberculosis has co-evolved with the human host, adapting to exploit the immune system for persistence and transmission. While immunity to tuberculosis (TB) has been intensively studied in the lung and lymphoid system, little is known about the participation of adipose tissues and non-immune cells in the host-pathogen interaction during this systemic disease. METHODS: C57BL/6J mice were aerosol infected with M. tuberculosis Erdman and presence of the bacteria and the fitness of the white and brown adipose tissues, liver and skeletal muscle were studied compared to uninfected mice. FINDINGS: M. tuberculosis infection in mice stimulated immune cell infiltration in visceral, and brown adipose tissue. Despite the absence of detectable bacterial dissemination to fat tissues, adipocytes produced localized pro-inflammatory signals that disrupted adipocyte lipid metabolism, resulting in adipocyte hypertrophy. Paradoxically, this resulted in increased insulin sensitivity and systemic glucose tolerance. Adipose tissue inflammation and enhanced glucose tolerance also developed in obese mice after aerosol M. tuberculosis infection. We found that infection induced adipose tissue Akt signaling, while inhibition of the Akt activator mTORC2 in adipocytes reversed TB-associated adipose tissue inflammation and cell hypertrophy. INTERPRETATION: Our study reveals a systemic response to aerosol M. tuberculosis infection that regulates adipose tissue lipid homeostasis through mTORC2/Akt signaling in adipocytes. Adipose tissue inflammation in TB is not simply a passive infiltration with leukocytes but requires the mechanistic participation of adipocyte signals.

Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects.

BACKGROUND: Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis. METHODS: We investigated in vitro and in vivo effects of metformin in humans. RESULTS: Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in vitro cellular metabolism while inhibiting the mammalian target of rapamycin targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation and increased phagocytosis activity. Metformin administered to healthy human volunteers led to significant downregulation of genes involved in oxidative phosphorylation, mammalian target of rapamycin signaling, and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to nonclassical monocytes. At a functional level, metformin lowered ex vivo production of tumor necrosis factor α, interferon γ, and interleukin 1ß but increased phagocytosis activity and reactive oxygen species production. CONCLUSION: Metformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis.

Lysine Deacetylases and Regulated Glycolysis in Macrophages.

Regulated cellular metabolism has emerged as a fundamental process controlling macrophage functions, but there is still much to uncover about the precise signaling mechanisms involved. Lysine acetylation regulates the activity, stability, and/or localization of metabolic enzymes, as well as inflammatory responses, in macrophages. Two protein families, the classical zinc-dependent histone deacetylases (HDACs) and the NAD-dependent HDACs (sirtuins, SIRTs), mediate lysine deacetylation. We describe here mechanisms by which classical HDACs and SIRTs directly regulate specific glycolytic enzymes, as well as evidence that links these protein deacetylases to the regulation of glycolysis-related genes. In these contexts, we discuss HDACs and SIRTs as key control points for regulating immunometabolism and inflammatory outputs from macrophages.

To Evaluate and Compare the Result of Ossiculoplasty Using Different Types of Graft Materials and Prosthesis in Cases of Ossicular Discontinuity in Chronic Suppurative Otitis Media Cases.

Chronic suppurative otitis media, with and without cholesteatoma, frequently results in disruption of the ossicular chain. The present study was designed to compare the outcome using autologous ossicle and titanium prosthesis in two groups of suitable patients presenting with chronic suppurative otitis media for middle ear reconstructive surgeries. A prospective study done from July 2012 to December 2013, at Mahatma Gandhi Medical College and Hospital, Sitapura, Jaipur (Rajasthan). The target group included patients with chronic suppurative otitis media admitted and planned for reconstructive middle ear surgery. The study group patients among the target group requiring certain ossicular reconstruction. The patients included were patients with CSOM with or without cholesteatoma in which there was ossicular discontinuity. The patients were divided in two groups A and B. In group A patients autologous incus was used and in group B titanium prosthesis either TORP or PORP was used for ossicular replacement. Out of 340 patients as target group, 88 patients were included in study group. Further 88 patients of study group, 51 patients were included in group A; rest 37 patients were included in group B. In group B patients partial ossicular replacement platinum prosthesis was used in 31 patients while in rest 6 patients a total ossicular replacement prosthesis was used. Out of 88 patients, 79 were primary cases and 9 were revision cases. Pre and post operative air bone gap were noted. Pre operatively both of the groups were identical in relation to air-bone gap. The postoperative air-bone gap was calculated as the difference between postoperative air conduction and preoperative bone conduction. On comparison of preoperative and post-operative hearing results there was improvement in air conduction threshold and air bone gap in both the groups. Post operatively difference in air bone gap closure between group A and group B was found statistically significant (P value = 0.032) suggesting better hearing outcomes after using titanium ossicular replacement prosthesis. On comparing partial or total ossicular replacement prosthesis no significant difference was found for the audiological outcome (P = 0.434). Various prognostic factors were also noted for air bone gap closure. Titanium ossicular replacement prosthesis have better outcome, and no significant difference found in audiological outcome for TORP and PORP.

Automated Identification of Core Regulatory Genes in Human Gene Regulatory Networks.

Human gene regulatory networks (GRN) can be difficult to interpret due to a tangle of edges interconnecting thousands of genes. We constructed a general human GRN from extensive transcription factor and microRNA target data obtained from public databases. In a subnetwork of this GRN that is active during estrogen stimulation of MCF-7 breast cancer cells, we benchmarked automated algorithms for identifying core regulatory genes (transcription factors and microRNAs). Among these algorithms, we identified K-core decomposition, pagerank and betweenness centrality algorithms as the most effective for discovering core regulatory genes in the network evaluated based on previously known roles of these genes in MCF-7 biology as well as in their ability to explain the up or down expression status of up to 70% of the remaining genes. Finally, we validated the use of K-core algorithm for organizing the GRN in an easier to interpret layered hierarchy where more influential regulatory genes percolate towards the inner layers. The integrated human gene and miRNA network and software used in this study are provided as supplementary materials (S1 Data) accompanying this manuscript.

Multitarget, quantitative nanoplasmonic electrical field-enhanced resonating device (NE2RD) for diagnostics.

Recent advances in biosensing technologies present great potential for medical diagnostics, thus improving clinical decisions. However, creating a label-free general sensing platform capable of detecting multiple biotargets in various clinical specimens over a wide dynamic range, without lengthy sample-processing steps, remains a considerable challenge. In practice, these barriers prevent broad applications in clinics and at patients' homes. Here, we demonstrate the nanoplasmonic electrical field-enhanced resonating device (NE(2)RD), which addresses all these impediments on a single platform. The NE(2)RD employs an immunodetection assay to capture biotargets, and precisely measures spectral color changes by their wavelength and extinction intensity shifts in nanoparticles without prior sample labeling or preprocessing. We present through multiple examples, a label-free, quantitative, portable, multitarget platform by rapidly detecting various protein biomarkers, drugs, protein allergens, bacteria, eukaryotic cells, and distinct viruses. The linear dynamic range of NE(2)RD is five orders of magnitude broader than ELISA, with a sensitivity down to 400 fg/mL This range and sensitivity are achieved by self-assembling gold nanoparticles to generate hot spots on a 3D-oriented substrate for ultrasensitive measurements. We demonstrate that this precise platform handles multiple clinical samples such as whole blood, serum, and saliva without sample preprocessing under diverse conditions of temperature, pH, and ionic strength. The NE(2)RD's broad dynamic range, detection limit, and portability integrated with a disposable fluidic chip have broad applications, potentially enabling the transition toward precision medicine at the point-of-care or primary care settings and at patients' homes.

Metformin as adjunct antituberculosis therapy.

The global burden of tuberculosis (TB) morbidity and mortality remains immense. A potential new approach to TB therapy is to augment protective host immune responses. We report that the antidiabetic drug metformin (MET) reduces the intracellular growth of Mycobacterium tuberculosis (Mtb) in an AMPK (adenosine monophosphate-activated protein kinase)-dependent manner. MET controls the growth of drug-resistant Mtb strains, increases production of mitochondrial reactive oxygen species, and facilitates phagosome-lysosome fusion. In Mtb-infected mice, use of MET ameliorated lung pathology, reduced chronic inflammation, and enhanced the specific immune response and the efficacy of conventional TB drugs. Moreover, in two separate human cohorts, MET treatment was associated with improved control of Mtb infection and decreased disease severity. Collectively, these data indicate that MET is a promising candidate host-adjunctive therapy for improving the effective treatment of TB.

Nonclassical T cells and their antigens in tuberculosis.

T cells that recognize nonpeptidic antigens, and thereby are identified as nonclassical, represent important yet poorly characterized effectors of the immune response. They are present in large numbers in circulating blood and tissues and are as abundant as T cells recognizing peptide antigens. Nonclassical T cells exert multiple functions including immunoregulation, tumor control, and protection against infections. They recognize complexes of nonpeptidic antigens such as lipid and glycolipid molecules, vitamin B2 precursors, and phosphorylated metabolites of the mevalonate pathway. Each of these antigens is presented by antigen-presenting molecules other than major histocompatibility complex (MHC), including CD1, MHC class I-related molecule 1 (MR1), and butyrophilin 3A1 (BTN3A1) molecules. Here, we discuss how nonclassical T cells participate in the recognition of mycobacterial antigens and in the mycobacterial-specific immune response.

T cell recognition of non-peptidic antigens in infectious diseases.

The immune system has evolved to recognize a wide range of antigenic molecules of self and non-self origin. The stimulatory antigens form complexes with antigen-presenting molecules and directly interact with the T cell receptor (TCR). Peptidic antigens associate with major histocompatibility complex (MHC) molecules and therefore, are indicated as MHC-restricted. Non-peptidic antigens do not bind to MHC molecules and are presented by other classes of antigen-presenting molecules. These non-MHC restricted antigens include glycolipid molecules, phosphorylated metabolites of the mevalonate pathway and vitamin B2 precursors. T cells specific for non-peptidic antigens have important roles in host defense against infections, autoimmunity, allergies and tumour immunosurveillance. Hence, understanding the molecular interactions between the antigen presenting cell (APC) and the T cells with non-peptidic specificity is of great relevance. Here, we review current knowledge of this type of T cells, their TCR repertoire, the structural aspects of recognized antigens, the mode of antigen recognition, and their function with special emphasis on their role in infectious diseases.

Perioperative risk factors in patients with liver disease undergoing non-hepatic surgery.

The patients with liver disease present for various surgical interventions. Surgery may lead to complications in a significant proportion of these patients. These complications may result in considerable morbidity and mortality. Preoperative assessment can predict survival to some extent in patients with liver disease undergoing surgical procedures. A review of literature suggests nature and the type of surgery in these patients determines the peri-operative morbidity and mortality. Optimization of premorbid factors may help to reduce perioperative mortality and morbidity. The purpose of this review is to discuss the effect of liver disease on perioperative outcome; to understand various risk scoring systems and their prognostic significance; to delineate different preoperative variables implicated in postoperative complications and morbidity; to establish the effect of nature and type of surgery on postoperative outcome in patients with liver disease and to discuss optimal anaesthesia strategy in patients with liver disease.

BCG induces protection against Mycobacterium tuberculosis infection in the Wistar rat model.

Our understanding of the correlation of Mycobacterium bovis Bacille Calmette-Guerin (BCG)-mediated immune responses and protection against Mycobacterium tuberculosis (Mtb) infection is still limited. We have recently characterized a Wistar rat model of experimental tuberculosis (TB). In the present study, we evaluated the efficacy of BCG vaccination in this model. Upon Mtb challenge, BCG vaccinated rats controlled growth of the bacilli earlier than unvaccinated rats. Histopathology analysis of infected lungs demonstrated a reduced number of granulomatous lesions and lower parenchymal inflammation in vaccinated animals. Vaccine-mediated protection correlated with the rapid accumulation of antigen specific CD4(+) and CD8(+) T cells in the infected lungs. Immunohistochemistry further revealed higher number of CD8(+) cells in the pulmonary granulomas of vaccinated animals. Evaluation of pulmonary immune responses in vaccinated and Mtb infected rats by real time PCR at day 15 post-challenge showed reduced expression of genes responsible for negative regulation of Th1 immune responses. Thus, early protection observed in BCG vaccinated rats correlated with a similarly timed shift of immunity towards the Th1 type response. Our data support the importance of (i) the Th1-Th2 balance in the control of mycobacterial infection and (ii) the value of the Wistar rats in understanding the biology of TB.

Liver abscess presentation and management in Saudi Arabia and the United Kingdom.

BACKGROUND AND OBJECTIVES: Liver abscess (LA) is a well-described disease in the medical literature; however, information about its characteristics and outcome in the Middle East is lacking. We compared the mode of presentation, risk factors, management and outcome of LA patients in Saudi Arabia with cases from the United Kingdom (UK). DESIGN AND SETTING: Retrospective review of LA patients from three tertiary care centers (2 from Saudi Arabia and 1 from the UK) over a period of 10 years, from 1995 to 2005. PATIENTS AND METHODS: Data collected included demographic characteristics; clinical presentation; biochemical, microbiological and radiological findings; treatment modalities; and outcome. RESULTS: A total of 83 patients were diagnosed with LA, including 48 patients from Saudi Arabia and 35 patients from the UK. The mean (SD) age was 45.2 (20.3) years for those from Saudi Arabia and 55.4 (18.8) years for those from the UK (P=.022). The majority of the patients were males (70% from Saudi Arabia and 80% from the UK). Upper abdominal pain and fever were the commonest symptoms, each reported in 87% of the cases. Alkaline phosphatase elevation was the commonest liver function abnormality, seen in 66 (80%) patients. Organisms were isolated in 43 (52%) cases and the majority of these were coliforms (58%). Amebic liver abscesses occurred in 19 (23%) patients and all of those patients were either from or had traveled recently to the Indian subcontinent. Complete resolution of the abscesses was achieved in 66 (80%) patients with aspiration and/or antibiotics, and 9 (10.8%) patients died. On multivariate analysis, underlying malignancy, hypotension and chest signs at presentation were predictors of poor outcome (P=.008, .029 and .001, respectively). CONCLUSIONS: Successful resolution of LA is achievable in the majority of the cases, although underlying malignancy is associated with poor outcome. Amebic liver abscesses must be considered in patients with a history of travel to endemic areas.

Mycobacterium tuberculosis infection induces hypoxic lung lesions in the rat.

Hypoxia is believed to influence the metabolic state of Mycobacterium tuberculosis and cause phenotypic drug resistance. Using pimonidazole adduct staining, we show that lung lesions of infected rats contain regions of low oxygen tension. Our results support the use of the rat model for evaluating anaerobic drug activity in vivo.