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Background: For pregnant women living with human immunodeficiency virus (HIV), concurrent active tuberculosis (TB) disease increases the risk of maternal mortality and poor pregnancy outcomes. Plasma indoleamine 2,3-dioxygenase (IDO) activity measured by kynurenine-to-tryptophan (K/T) ratio has been proposed as a blood-based TB biomarker. We investigated whether plasma K/T ratio could be used to diagnose active TB among pregnant women with HIV., Methods: Using an enzyme-linked immunosorbent assay (ELISA), we measured K/T ratio in 72 pregnant women with and active TB and compared them to 117 pregnant women with HIB but without TB, matched by age and gestational age., Results: Plasma K/T ratio was significantly elevated during pregnancy compared to sampling done after pregnancy (P < .0001). Pregnant women who had received isoniazid preventive therapy (IPT) before enrollment had decreased plasma K/T ratio compared to those who had not received IPT (P = .0174). Plasma K/T ratio was elevated in women with active TB at time of diagnosis compared to those without TB (P < .0001). Using a cutoff of 0.100, plasma K/T ratio gave a diagnostic sensitivity of 94% (95% confidence interval [CI]: 82-95), specificity of 90% (95% CI: 80-91), positive predictive value (PPV) 85% and negative predictive value (NPV) 98%. A receiver operating characteristic curve (ROC) gave an area under the curve of 0.95 (95% CI: .92-.97, P < .0001).In conclusion, plasma K/T ratio is a sensitive blood-based diagnostic test for active TB disease in pregnant women living with HIV. Plasma K/T ratio should be further evaluated as an initial TB diagnostic test to determine its impact on patient care., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The interaction between COVID-19, non-communicable diseases, and chronic infectious diseases such as HIV and tuberculosis is unclear, particularly in low-income and middle-income countries in Africa. South Africa has a national HIV prevalence of 19% among people aged 15-49 years and a tuberculosis prevalence of 0·7% in people of all ages. Using a nationally representative hospital surveillance system in South Africa, we aimed to investigate the factors associated with in-hospital mortality among patients with COVID-19., Methods: In this cohort study, we used data submitted to DATCOV, a national active hospital surveillance system for COVID-19 hospital admissions, for patients admitted to hospital with laboratory-confirmed SARS-CoV-2 infection between March 5, 2020, and March 27, 2021. Age, sex, race or ethnicity, and comorbidities (hypertension, diabetes, chronic cardiac disease, chronic pulmonary disease and asthma, chronic renal disease, malignancy in the past 5 years, HIV, and past and current tuberculosis) were considered as risk factors for COVID-19-related in-hospital mortality. COVID-19 in-hospital mortality, the main outcome, was defined as a death related to COVID-19 that occurred during the hospital stay and excluded deaths that occurred because of other causes or after discharge from hospital; therefore, only patients with a known in-hospital outcome (died or discharged alive) were included. Chained equation multiple imputation was used to account for missing data and random-effects multivariable logistic regression models were used to assess the role of HIV status and underlying comorbidities on COVID-19 in-hospital mortality., Findings: Among the 219 265 individuals admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and known in-hospital outcome data, 51 037 (23·3%) died. Most commonly observed comorbidities among individuals with available data were hypertension in 61 098 (37·4%) of 163 350, diabetes in 43 885 (27·4%) of 159 932, and HIV in 13 793 (9·1%) of 151 779. Tuberculosis was reported in 5282 (3·6%) of 146 381 individuals. Increasing age was the strongest predictor of COVID-19 in-hospital mortality. Other factors associated were HIV infection (adjusted odds ratio 1·34, 95% CI 1·27-1·43), past tuberculosis (1·26, 1·15-1·38), current tuberculosis (1·42, 1·22-1·64), and both past and current tuberculosis (1·48, 1·32-1·67) compared with never tuberculosis, as well as other described risk factors for COVID-19, such as male sex; non-White race; underlying hypertension, diabetes, chronic cardiac disease, chronic renal disease, and malignancy in the past 5 years; and treatment in the public health sector. After adjusting for other factors, people with HIV not on antiretroviral therapy (ART; adjusted odds ratio 1·45, 95% CI 1·22-1·72) were more likely to die in hospital than were people with HIV on ART. Among people with HIV, the prevalence of other comorbidities was 29·2% compared with 30·8% among HIV-uninfected individuals. Increasing number of comorbidities was associated with increased COVID-19 in-hospital mortality risk in both people with HIV and HIV-uninfected individuals., Interpretation: Individuals identified as being at high risk of COVID-19 in-hospital mortality (older individuals and those with chronic comorbidities and people with HIV, particularly those not on ART) would benefit from COVID-19 prevention programmes such as vaccine prioritisation as well as early referral and treatment., Funding: South African National Government., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Human enteroviruses (EV) consist of 106 serotypes and four species: EV-A, EV-B, EV-C and EV-D. Enteroviruses cause clinical symptoms varying from severe to mild. Knowledge of EV burden in South Africa is limited, and as non-polio EV are important causes of acute flaccid paralysis (AFP) and meningitis, information on the circulating serotypes is vital., Methods: Between 2010 and 2012, a total of 832 stool and viral isolate specimens were obtained from two national surveillance programmes at the National Institute for Communicable Diseases: the Rotavirus Sentinel Surveillance Programme (RSSP) and the AFP surveillance programme. Real-time polymerase chain reaction and Sanger sequencing were performed to detect and serotype EV., Results: Non-polio EV were detected in 446 specimens, of which 308 were sequenced. Stool specimens yielded a greater variety of serotypes than viral cultures. EV-B viruses were predominant (58.44%), whilst EV-C viruses were detected in 31% of the specimens tested. South African prevalence for these viruses was higher than other countries, such as France with less than 2%, and Spain and the United States with less than 10%. The most common serotype detected was Enterovirus 99 (EV-C, 8.63%), which has not been reported in other regions., Conclusion: Direct sequencing from stool specimens yields a broader, more comprehensive description of EV infections compared to sequencing from viral cultures. Disease-associated serotypes were detected, but only in small numbers. This study provides a baseline for EV strain circulation; however, surveillance needs to be expanded to improve EV knowledge in South Africa., Competing Interests: The authors have declared that no competing interests exist., (© 2020. The Authors.)

Introduction: The World Health Organization has identified the need for a non-sputum-based test capable of detecting active tuberculosis (TB) as a priority. The plasma kynurenine-to-tryptophan (K/T) ratio, largely mediated by activity of the enzyme indoleamine 2,3-dioxygenase, may have potential as a suitable biomarker for active TB., Method: We evaluated a commercial enzyme-linked immunosorbent assay (ELISA) in comparison to mass spectrometry for measuring the K/T ratio. We also used ELISA to determine the K/T ratio in plasma from patients with active TB compared to latently infected controls, with and without HIV., Results: The two methods showed good agreement, with a mean bias of 0.01 (limit of agreement from -0.06 to 0.10). Using ELISA, it was found that HIV-infected patients with active TB disease had higher K/T ratios than those without TB (median, 0.101 [interquartile range (IQR), 0.091-0.140] versus 0.061 [IQR, 0.034-0.077], P<0.0001). At a cutoff of 0.080, the K/T ratio produced a sensitivity of 90%, a specificity of 80%, a positive predictive value (PPV) of 82%, and a negative predictive value (NPV) of 90%. In a receiver operating characteristics analysis, the K/T ratio had an area under the curve of 0.93. HIV-uninfected patients with active TB also had higher K/T ratios than those with latent TB infections (median, 0.064 [IQR, 0.040-0.088] versus 0.022 [IQR, 0.016-0.027], P<0.0001). A cutoff of 0.040 gave a sensitivity of 85%, a specificity of 92%, a PPV of 91%, and an NPV of 84%., Conclusion: The plasma K/T ratio is a sensitive biomarker for active TB. The K/T ratio can be measured from blood using ELISA. The K/T ratio should be evaluated as an initial test for TB., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Progression from latency to active Tuberculosis (TB) disease is mediated by incompletely understood host immune factors. The definitive characteristic of progressive human immunodeficiency virus (HIV) disease is a severe loss in number and function of T lymphocytes. Among the many possible mediators of T lymphocyte loss and ineffective function is the activity of the immune-modulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO is the rate-limiting enzyme converting tryptophan to kynurenine. IDO activity was initially recognized to mediate tolerance at the foeto-maternal interface. Recently, IDO activity has also been noted to play a critical role in immune tolerance to pathogens. Studies of host immune and metabolic mediators have found IDO activity significantly elevated in HIV and TB disease. In this review, we explore the link between IDO-mediated tryptophan catabolism and the presence of active TB disease in HIV-infected patients. We draw attention to increased IDO activity as a key factor marking the progression from latent to active TB disease in HIV-infected patients., (Copyright © 2019 Adu-Gyamfi, Savulescu, George and Suchard.)

Unlabelled: Oxidative stress and metalloproteinase (MMPs) may have a pivotal role in the pathogenesis of epilepsy. This study examined the underlying mechanism of epilepsy in children and especially in its intractable form, with respect to the roles of MMP's and free radicals in general and in saliva in particular. We also explored the possible diagnostic role of a compositional salivary analysis in these children, as salivary collection is simple, non-invasive (and thus 'children-friendly') and requires almost no expertise. We analyzed saliva parameters of 33 epileptic children: 22 with non-intractable (E's) and 11 with intractable epilepsy (IE's), and compared them with 16 healthy controls. Mean salivary LDH concentration in controls was 213.1±34.0IU/L, dropping by 38% (p=0.014) in E's and by 76% (p=0.0003) in IE's. Mean salivary values of peroxidase activity, SOD activity and carbonyls level were 480±14mU/mL, 1.30±0.15U/mL and 0.34±0.04nmol/mg, respectively, in controls, increasing by 6% (p=0.03), by 37% (p=0.04) and by 59% (p=0.003) in E's, and by 10% (p=0.02), by 29% (p=0.03) and by 56% (p=0.004) in IE's. Mean salivary MMP 9 concentration was 0.062±0.003 (OD) in controls, decreased by 12% (p=0.048) in E's, and by 23%, (p=0.009) in IE's. Our results enhance our understanding of epilepsy's biological underlying mechanism as reflected in the saliva of children with both intractable and non intractable disease., Significance: The currently reported salivary analysis and the demonstrated salivary alterations in children suffering from epilepsy represent a novel direction. We found various salivary alterations demonstrated in the general composition as well as the oxidative and metalloproteinase analyses and more so in the intractable epilepsy group than in the non intractable epilepsy group. Hence, salivary oxidative components and MMP levels were found useful in the detection and follow-up of children with epilepsy. As such, we recommend using this non-invasive salivary analysis for diagnosis and monitoring of epileptic activity in children., (Copyright © 2013 Elsevier B.V. All rights reserved.)

GnRH regulates circulating levels of the gonadotropins but has also been implicated in establishing the gonadotrope cell population. Consistent with this, GnRH induces proliferation of partially differentiated gonadotropes, while reducing the numbers of fully differentiated cells. We have previously reported that the proapoptotic protein, prohibitin (PHB) is expressed more abundantly in gonadotrope-derived LβT2 cells than in partially differentiated αT3-1 gonadotrope precursor cells, suggesting a possible role for PHB in GnRH-induced apoptosis. We show here that PHB is required for GnRH-induced apoptosis in mature gonadotropes. PHB expression and activity are regulated by GnRH: its transcription is via c-Jun NH2-terminal kinase, whereas its nuclear export follows activation of ERK. Moreover, PHB levels are down-regulated by microRNA27, which is expressed at lower levels in mature gonadotropes, possibly explaining the switch to an apoptotic response with development. PHB is required for mitochondrial import of the proapoptotic BAX, whose expression is also induced by GnRH-activated c-Jun NH2-terminal kinase, as is expression of the BH3-only protein, HRK, and this too plays a role in GnRH-induced apoptosis. Finally, we show that gonadotrope-specific PHB-knockout mice display reproductive abnormalities, including a larger gonadotrope population, increased LH levels, reduced fertility, and altered gonad development. We thus demonstrate a role for PHB in GnRH-induced cell death in mature gonadotropes, which is crucial for the normal development and function of the reproductive axis.

Background: Prolonged surgical procedures involving stress, extended general anaesthesia and a long pre-surgical fasting period may have systemic effects such as alterations in saliva flow rate and composition. These may compromise the patient's electrolytes and fluid balance and cause dehydration, systemic stress and oxidative changes., Patients and Methods: Saliva was collected prior and following surgery from 20 patients and 20 control subjects. The saliva samples were analysed for flow rates and levels of the following: calcium (Ca), magnesium (Mg), total protein, albumin and lactate dehydrogenase (LDH), total antioxidant status (TAS), uric acid (UA), superoxide dismutase (SOD), carbonyls, matrix metalloproteinases (MMPs) -2, -3 and -9 and heat shock proteins (HSPs) 70 and 90., Results: Salivary levels of Ca, Mg, protein, albumin and LDH were higher in post-surgical patients by 70% (P = 0·002), 88% (P = 0·0001), 120% (P = 0·13), 111% (P = 0·039) and 492% (P = 0·006) respectively than that in healthy controls. Salivary antioxidants in the surgical patients were higher while salivary carbonyls remained unchanged. Salivary TAS levels in pre- and post-surgical patients were higher by 63% (P = 0·001) and 85% (P = 0·0001) respectively, UA concentrations by 92% (P = 0·014) and 81% (P = 0·036) respectively and SOD values by 47% (P = 0·61) and 112% (P = 0·049) respectively. Salivary concentrations of MMP3 were higher in pre- and post-surgical patients by 23% (P = 0·067) and 30% (P = 0·044) respectively., Conclusions: Local salivary, oral and systemic-induced alterations should be prevented. Moreover, salivary collection and analysis may be a new, efficient tool in the monitoring of patients undergoing major surgery. Further related research is necessary., (© 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.)

Oral cancer features high rates of mortality and morbidity, and is in dire need for new approaches. In the present study we analyzed 18 kDa translocator protein (TSPO) expression in oral (tongue) cancer tumors by immunohistochemistry. We also assayed TSPO binding in human tongue cancer cell lines and in the cellular fraction of saliva from tongue cancer patients, heavy cigarette smokers, and non-smoking healthy people as controls. Concurrently, TSPO protein levels, cell viability, mitochondrial membrane potential (Deltapsi(m)), and general protein levels were analyzed. TSPO expression could be significantly enhanced in oral cancer tumors, compared to unaffected adjacent tissue. We also found that five-year survival probability dropped from 65% in patients with TSPO negative tumors to 7% in patients with highly expressed TSPO (p<0.001). TSPO binding capacity was also pronounced in the human oral cancer cell lines SCC-25 and SCC-15 (3133+/-643 fmol/mg protein and 6956+/-549 fmol/mg protein, respectively). Binding decreased by 56% and 72%, in the SCC-25 and SCC-15 cell lines, respectively (p<0.05) following CS exposure in cell culture. In the cellular fraction of saliva of heavy smokers TSPO binding was lower than in non-smokers (by 53%, p<0.05). Also the cellular fraction of saliva exposed to CS in vitro showed decreased TSPO binding compared to unexposed saliva (by 30%, p<0.001). Interestingly, oral cancer patients also displayed significantly lower TSPO binding in the cellular fraction of saliva compared to healthy controls (by 40%, p<0.01). Our results suggest that low TSPO binding found in the cellular fraction of saliva may depend on genetic background as well as result from exposure to CS. We suggest that this may be related to a predisposition for occurrence of oral cancer., (Copyright 2010 Elsevier B.V. All rights reserved.)

Juvenile idiopathic arthritis (JIA) is the most common autoimmune inflammatory disease in children; joint inflammation is the hallmark of the disease. Thirty-five children with JIA were studied, of whom 26 had active disease and 14 were receiving anti-TNF therapy (5 with Infliximab, 9 with Etanercept). Sixteen healthy controls also were studied. Saliva samples were obtained for analysis of anti-oxidant status, metalloproteinases (MMPs) and sialochemistry. The total antioxidant status was significantly higher in the saliva of all JIA patients, whether treated (P = 0.014) or not treated (P = 0.038) with anti-TNF agents. The increase in antioxidant status (TAS) in the saliva of the active patients was nearly two times higher than that of non-active patients (P = 0.01). MMP levels were significantly lower in JIA patients than in controls. MMP-9, MMP-3 and MMP-2 were lower in JIA patients without anti-TNF treatment by 36.7% (P = 0.01), 30.0% (P = 0.0001) and 10.7% (P = 0.0001), respectively. A greater reduction in MMP levels was observed in the group of patients treated with anti-TNF drugs: MMP-9, MMP-3 and MMP-2 were lower than in controls by 51.1% (P = 0.0001), 61.5% (P = 0.0001) and 55.4% (P = 0.0001), respectively. Children with JIA exhibited a significantly higher salivary antioxidant activity and significantly lower MMP levels. Anti-TNF treatment was associated with a further decrease in MMP levels in the saliva of JIA patients while an active state of JIA was associated with a further increase in the salivary antioxidant activity. Anti-TNF treatment may modulate the degradation process during the course of arthritis by inhibition of the activity of MMP.

Background: Cigarette smoke (CS) is the major risk factor for aerodigestive tract cancers such as lung and oral cancers., Methods: In in vitro models of lung and oral cancers, we found D-penicillamine (PenA) to be a most potent protector against CS, both in the absence and presence of saliva (a highly pro-oxidative condition)., Results: The survival rate of lung cancer cells and oral cancer cells was reduced by CS in the absence of saliva by 39-45% (p < 0.01) and by 55-60% (p < 0.01) in the presence of saliva. The addition of 5 mM PenA to cell medium prior to CS exposure limited cell loss to 22-25% only (p < 0.01). Similarly, the iron chelator desferal protected the cells only in the presence of saliva. PenA also protected against a CS-induced increase in carbonyls (oxidized proteins) and decrease in p53 levels (in the presence of saliva) and mitochondrial membrane potential (a hallmark of CS-induced apoptotic cell death). Malfunctioning p53 often characterizes carcinogenesis of CS-induced cancers., Conclusions: Redox-active iron and copper in pleural fluid and saliva, upon encounter with CS, may be responsible for this carcinogenesis, mediated via alteration of p53 function. Chelation of redox-active metals may be an efficient tool for prevention of CS-induced lung and oral cancers. The superiority of PenA results from its copper-chelating action as well as its antialdehyde and anti-inflammatory capabilities., (Copyright 2010 S. Karger AG, Basel.)