Immunologic and imaging signatures in post tuberculosis lung disease.

Post Tuberculosis Lung Disease (PTLD) affects millions of tuberculosis survivors and is a global health burden. The immune mechanisms that drive PTLD are complex and have historically been under investigated. Here, we discuss two immune-mediated paradigms that could drive human PTLD. We review the characteristics of a fibrotic granuloma that favors the development of PTLD via an abundance of T-helper-2 and T-regulatory cells and an upregulation of TGF-ß mediated collagen deposition. Next, we discuss the post-primary tuberculosis paradigm and the complex mixture of caseous pneumonia, cavity formation and fibrosis that can also lead to PTLD. We review the delicate balance between cellular subsets and cytokines of the innate and adaptive immune system in conjunction with host-derived proteases that can perpetuate the parenchymal lung damage seen in PTLD. Next, we discuss the role of novel host directed therapies (HDT) to limit the development of PTLD and in particular, the recent repurposing of established medications such as statins, metformin and doxycycline. Finally, we review the emerging role of novel imaging techniques as a non-invasive modality for the early recognition of PTLD. While access to computed tomography imaging is unlikely to be available widely in countries with a high TB burden, its use in research settings can help phenotype PTLD. Due to a lack of disease-specific biomarkers and controlled clinical trials, there are currently no evidence-based recommendations for the management of PTLD. It is likely that an integrated antifibrotic strategy that could simultaneously target inflammatory and pro-fibrotic pathways will probably emerge as a successful way to treat this complex condition. In a disease spectrum as wide as PTLD, a single immunologic or radiographic marker may not be sufficient and a combination is more likely to be a successful surrogate that could aid in the development of successful HDTs.

Elevated Plasma Matrix Metalloproteinase 8 Associates With Sputum Culture Positivity in Pulmonary Tuberculosis.

Current methods for tuberculosis treatment monitoring are suboptimal. We evaluated plasma matrix metalloproteinase (MMP) and procollagen III N-terminal propeptide concentrations before and during tuberculosis treatment as biomarkers. Plasma MMP-1, MMP-8, and MMP-10 concentrations significantly decreased during treatment. Plasma MMP-8 was increased in sputum Mycobacterium tuberculosis culture-positive relative to culture-negative participants, before (median, 4993 pg/mL [interquartile range, 2542-9188] vs 698 [218-4060] pg/mL, respectively; P = .004) and after (3650 [1214-3888] vs 720 [551-1321] pg/mL; P = .008) 6 months of tuberculosis treatment. Consequently, plasma MMP-8 is a potential biomarker to enhance tuberculosis treatment monitoring and screen for possible culture positivity.

Treatment of tuberculous meningitis in adults: Is the duration of intensive-phase therapy adequate?

Tuberculous meningitis (TBM) results in considerable morbidity and mortality, especially in developing countries such as South Africa. Treatment regimens have been extrapolated from treatment for pulmonary tuberculosis, and the intensive-phase duration of 2 months may be inadequate for treatment of patients with TBM. We highlight this situation with a case report of a patient with TBM whose illness progressed after institution of the maintenance phase of treatment. We propose that the intensive-phase treatment of TBM be revisited with regard to duration of treatment, choice of drugs during continuation-phase therapy, or both.

A retrospective description of primary immuno-deficiency diseases at Red Cross War Memorial Children's Hospital, Cape Town, South Africa, 1975 - 2017.

BACKGROUND: The primary immunodeficiency diseases (PIDs) constitute a diverse and ever-expanding group of inborn errors affecting a wide range of immune functions. They are not well documented in sub-Saharan Africa. OBJECTIVES: To describe the spectrum of PIDs at a tertiary paediatric hospital. METHODS: A retrospective descriptive study of PIDs diagnosed at Red Cross War Memorial Children's Hospital, Cape Town, South Africa (SA), between 1975 and 2017 was undertaken. RESULTS: We identified 252 children with PIDs, spanning eight of the nine categories listed in the 2017 classification of the International Union of Immunological Societies. Predominantly antibody deficiencies, combined immunodeficiencies with associated syndromic features, and immunodeficiencies affecting cellular and humoral immunity accounted for most children with PIDs (n=199, 79.0%). The mean age (standard deviation) at diagnosis was 46 (50) months, and the male/female ratio was 1.5:1. There was a history of parental consanguinity in 3 cases (1.2%). Recurrent infection was the most prevalent presenting phenotype, manifesting in 177 patients (70.2%). Genetic or chromosomal confirmation was obtained in 42/252 cases (16.7%). Common interventions used to prevent infection were antimicrobial prophylaxis and immunoglobulin replacement therapy, administered to 95 (37.7%) and 93 (36.9%) of the patients, respectively. Six of 7 children who underwent haematopoietic stem cell transplantation (HSCT) had successful outcomes. The 7th patient died 2 months after HSCT from overwhelming infection. Although we could not account for the children lost to follow-up during the study period, 53 deaths were confirmed (21.0%). CONCLUSIONS: Several challenges exist in the recognition and treatment of children with PIDs in our setting. These include limited access to genetic diagnostics and HSCT. Suboptimal treatment options contribute to the overall mortality of PIDs in SA.

Maternal arterial stiffness and fetal cardiovascular physiology in diabetic pregnancy.

OBJECTIVES: In mothers with pregestational or gestational diabetes, abnormal arterial stiffness (stiffer arteries) has been reported. The impact of abnormal maternal arterial stiffness on placental and fetal cardiovascular physiology is unknown. The purpose of this study was to determine the impact of maternal diabetes on maternal arterial stiffness and the association with fetal cardiovascular physiology as measured by fetal echocardiography. METHODS: Between December 2013 and January 2017 a prospective study was conducted on diabetic (but otherwise healthy) and non-diabetic, healthy pregnant mothers aged 18-40 years at 20-28 weeks' gestation who had a normal fetal cardiac echocardiogram and obstetric ultrasound. Clinical data were collected by means of a patient questionnaire and measurement of blood pressure, height, weight, arterial augmentation index (AIx) and placental and fetal cardiovascular parameters were collected by fetal echocardiography. Descriptive statistics were calculated. Comparisons were made using parametric and non-parametric tests between controls and diabetic mothers. RESULTS: Twenty-three healthy pregnant controls and 43 diabetic pregnant women (22 with pregestational and 21 with gestational diabetes) were included in the study. Maternal AIx was higher in those with diabetes than in healthy controls (12.4 ± 10.6% vs 4.6 ± 7.9%; P = 0.003). Fetal aortic valve (AoV) velocity time integral (VTI) was higher in fetuses whose mothers had diabetes than in those with non-diabetic mothers (7.7 ± 1.9 cm vs 6.3 ± 3.0 cm; P = 0.022). Left ventricular (LV) myocardial performance index (MPI) was lower in diabetic pregnancies than in controls (0.40 ± 0.09 vs 0.46 ± 0.11; P = 0.021). Umbilical artery (UA) resistance index (RI) was lower in diabetic pregnancies with glycated hemoglobin (HbA1c) levels ≥ 6.5% than in those with HbA1c levels < 6.5% (0.69 ± 0.06, n = 15 vs 0.76 ± 0.08, n = 21; P = 0.009) but not at higher HbA1C cut-offs. No correlation between AIx and AoV-VTI, LV-MPI or UA-RI was found. CONCLUSIONS: Arterial stiffness is higher in pregnant women with diabetes than in controls. Fetuses of diabetic mothers show altered cardiovascular parameters, with higher AoV-VTI and lower LV-MPI, which are markers of myocardial function. Placental function assessed by UA-RI was normal despite differences between groups. Arterial stiffness did not correlate with placental or fetal cardiovascular variables. Instead, the findings are likely to represent a shared response to the environment of abnormal glucose metabolism. The clinical significance of these findings is yet to be determined. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

South African Menopause Society revised consensus position statement on menopausal hormone therapy, 2014.

The South African Menopause Society (SAMS) consensus position statement on menopausal hormone therapy (HT) 2014 is a revision of the SAMS Council consensus statement on menopausal HT published in the SAMJ in May 2007. Information presented in the previous statement has been re-evaluated and new evidence has been incorporated. While the recommendations pertaining to HT remain similar to those in the previous statement, the 2014 revision includes a wider range of clinical benefits for HT, the inclusion of non-hormonal alternatives such as selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors for the management of vasomotor symptoms, and an appraisal of bioidentical hormones and complementary medicines used for treatment of menopausal symptoms. New preparations that are likely to be more commonly used in the future are also mentioned. The revised statement emphasises that commencing HT during the 'therapeutic window of opportunity' maximises the benefit-to-risk profile of therapy in symptomatic menopausal women.

Expression of HLA-G1 at the placental interface of HIV-1 infected pregnant women and vertical transmission of HIV.

OBJECTIVES: The ability of Human Leucocyte Antigen-G (HLA-G) to inhibit the cytolytic effect to immunocompetent cell types, suggests that HLA-G has an immunomodulatory role. In view of this concept the objective of the study was to assess whether the Major Histocompatibility Complex -coded molecule HLA-G mRNA is a risk factor at the placental barrier in HIV-1 positive pregnant women. DESIGN: Placental HLA-G1 levels in HIV-1 infected mothers and viral loads in both mothers and their babies were performed on fifty-five participants. METHODS: Synthesis of complementary deoxyribose nucleic acid (cDNA) was performed using ribose nucleic acid (RNA) extracted from placental tissue samples. Amplification of cDNA using specifically designed primers complementary to the full length HLA-G1 isoform was quantified using real time-polymerase chain reaction (RT-PCR). Viral load assays (Amplicor Version 1.5, Roche Diagnostics) were performed on all plasma samples. RESULTS: HLA-G1 primers detected the full length isoform HLA-G1 PCR product at 86.5 °C. Logistic regression calculations indicated that the risk of babies becoming infected increased by 1.3 with every 1 unit increase in HLA-G1 expression. Female babies were 3.7 times more likely to become infected than male. There was a positive correlation between mothers' log viral load and transmission of infection to the baby (p = 0.047; 95%CI 1.029-11.499). CONCLUSION: Maternal viral load was a strong predictor of viral transmission. Placental HLA-G1 expression was up-regulated 3.95 times more in placentas of HIV-1 infected mothers with infected babies when compared to uninfected babies.

Direct admission versus inter-hospital transfer to a level I trauma unit improves survival: an audit of the new Inkosi Albert Luthuli Central Hospital trauma unit.

OBJECTIVE: To audit the performance of a new level I trauma unit and trauma intensive care unit. METHODS: Data on patients admitted to the level I trauma unit and trauma intensive care unit at Inkosi Albert Luthuli Central Hospital, Durban, from March 2007 to December 2008 were retrieved from the hospital informatics system and an independent database in the trauma unit. RESULTS: Four hundred and seven patients were admitted; 71% of admissions were inter-hospital transfers (IHT) and 29% direct from scene (DIR). The median age was 27 years (range 1 - 83), and 71% were male. Blunt injury accounted for 66.3% of admissions and penetrating trauma for 33.7%. Of the former, motor vehicle-related injury accounted for 87.4%, with 81% of paediatric admissions due to pedestrian-related injuries. The median injury severity score (ISS) for the entire cohort was 22 (survivors 18, deaths 29; p<0.001). Patients in the DIR group had a significantly higher mean ISS compared with the IHT group (DIR 25, IHT 20; p<0.02). The overall mortality rate was 26.3%. There were 37 deaths (31.1%) in the DIR group and 70 (24.3%) in the IHT group (p=0.19). In patients surviving more than 12 hours the overall mortality rate was 21.1% (DIR 13.7%, IHT 23.5%; p=0.042). CONCLUSIONS: Trauma is a major cause of premature death in the young. Despite a significantly higher median ISS in direct admissions, there was no difference in mortality. Of those surviving more than 12 hours, patients admitted directly had a significant decrease in mortality. Dedicated trauma units improve outcome in the critically injured.

A randomized, placebo-controlled, double-blind phase 2 study of docetaxel compared to docetaxel plus zosuquidar (LY335979) in women with metastatic or locally recurrent breast cancer who have received one prior chemotherapy regimen.

PURPOSE: To determine if concomitant administration of docetaxel plus zosuquidar.3HC1 can prolong progression-free survival in patients with metastatic breast cancer. METHODS: A randomized, double-blind, multicenter, placebo-controlled clinical trial comparing docetaxel plus 500 mg zosuquidar.3HCl (DZ) with docetaxel plus placebo (DP). RESULTS: A total of 170 patients were enrolled and randomly assigned to treatment. The median age was 53 years (range, 31-74 years). 81.7% of patients had prior chemotherapy in the adjuvant setting and 18.3% in the neoadjuvant setting. The median progression-free survival time was statistically different between groups [7.2 months (DZ) vs. 8.3 months (DP)]. Once the stratification factor relative to progression following prior chemotherapy was considered, no significant treatment difference existed. CONCLUSION: The combination of zosuquidar.3HCl plus docetaxel is safe. The analysis of efficacy data is complex, but it can be concluded that there is no difference in progression-free survival, overall survival, or response rate in the study as a whole.

Wound healing assessment using 20 MHz ultrasound and photography.

BACKGROUND/AIMS: To compare two non-invasive techniques of assessing wound healing, photography and high resolution ultrasound (HRUS) scanning, in experimentally induced full-thickness human skin wounds. METHODS: Punch biopsy wounds, 4 mm in diameter, were made aseptically through locally anaesthetised skin on the anterior (volar) surface of the non-dominant forearm, 3 cm below the base of the cubital fossa, of 20 human participants. The wounds were treated with a topical antibiotic and covered for 3 days with Mepore sterile dressings. Wound healing was assessed on post-operative days 3, 7, 14 and 21 from photographs and HRUS B-scans. All photographs were taken of the wound site and adjacent intact skin under standardised conditions. The prints obtained were examined visually and digitised. Digital HRUS B-scans were taken through the centre of the wound bed and the adjacent intact skin parallel to the epidermis. Using the scanner's calibrated linear measurement capability, the wound width was measured adjacent to the deep surface of the scab, at the base of the wound, and midway between these two levels. RESULTS: The wound margins were more clearly defined in the HRUS scans than in the photographs of the wounds; in some of the latter the scab masked the wound margins. Changes in the surface width of the wound were affected by the time of scab dehiscence, which varied between volunteers. There was less individual variation in the width of the base of the wound, as measured from the HRUS scans. CONCLUSIONS: In contrast to photography, which allows recording of changes in the superficial aspect of the wound only, HRUS scanning permits the quantitative assessment of structural changes deep within the wound. Temporal changes in the width of the base of the wound can be used as an indication of the progress of repair.

Use of the CID W22 as a South African English speech discrimination test.

South Africa currently lacks a pre-recorded South African English (SAE) specific speech discrimination test. In the absence of such a test, the SAE speaker recording (Tygerberg recording) of the American (USA) English (AE) CID W22 wordlists--in combination with the original American CID W22 normative data--is the most widely used alternative. The reliability and validity of this method, however, has never been formally assessed. This study assessed the performance of 15 normal hearing, female, first language SAE speakers on the first two full-lists of Tygerberg CID W22 recording at 20, 30, 40, 50, 60 and 70 dBSPL, and compared their scores to the American CID W22 wordlist normative data. Overall, the South African subjects performed worse than the original American normative data at the lower presentation intensities (< 50 dBSPL). Use of the Tygerberg CID W22 recording--with the original American CID W22 normative data--for near threshold assessment of SAE speaking subjects was therefore concluded to be problematic. Use at suprathreshold intensities (> 40 dBSPL), however, was considered a viable option. These results reiterate the need for large scale, South African specific normative studies for the CID W22 wordlists if they are to continue their role as the dominant speech discrimination wordlists in South Africa.

The use of a side effect as a qualitative indicator of plasma chlorpromazine levels.

Chlorpromazine (CPZ) is widely used in South African hospitals. The purpose of this study was to determine whether any physiological parameter (side-effect) could be correlated with plasma concentrations of CPZ or its metabolites. In the absence of a blood level, such a correlation could serve as a qualitative indicator of the amount of chlorpromazine in the body. Such a marker can assist the psychiatrist with therapeutic decisions regarding poor compliance and the lack of response with the drug. Fifteen schizophrenic patients were included in this study and regression analysis was used to determine any correlation between CPZ, 7-hydroxychlorpromazine, Chlorpromazine-N-oxide, Nor1 chlorpromazine, Nor2 chlorpromazine, chlorpromazine sulfoxide, Nor2 chlorpromazine sulfoxide and blood pressure, pulse rate, sedation and finger tremor. No correlation was seen between blood pressure or pulse rate and plasma concentrations of CPZ or the metabolites. A good correlation was seen between sedation, 7- hydroxychlorpromazine (P=0.035) and chlorpromazine sulfoxide (P=0.016). The results suggest that as the levels of chlorpromazine sulfoxide increase, the probability of sedation increases, while increasing levels of 7-hydroxychlorpromazine have the opposite effect. A good correlation was also seen between finger tremor and chlorpromazine levels (P=0.035). These results suggest that there is a 50% probability that the patient would experience finger tremor when the plasma concentration of chlorpromazine is 46 ng/ml. This study demonstrated the potential for the use of sedation and finger tremor as qualitative indicators of the plasma concentration of CPZ and two metabolites. Further studies with larger patient numbers are warranted.

The effect of tonsillectomy on eustachian tube function.

A two-part study was designed to investigate the effect of tonsillectomy on eustachian tube function and to identify if any change is related to postoperative pain. Middle ear pressure was measured by tympanometry and results were classified as type A (+50 daPa to -99 daPa), type B (flat) or type C (-100 daPa to -350 daPa). Thirty-one patients with type A tympanograms, undergoing tonsillectomy enrolled in study A. Patients had tympanometry the next day and filled in a questionnaire incorporating visual analogue pain scores. In study B, 30 patients underwent a similar protocol and were followed up at 1 week tympanometry and a questionnaire. A control group of 26 patients undergoing appendicectomy was recruited. Follow-up was available on 23 patients from study B. Combining A and B, on the first postoperative day 39% of patients developed type C tympanograms. No member of the control group developed any change in middle ear pressure. There was no significant relationship between pain scores for throat pain or otalgia and the development of negative middle ear pressure. By day 7 all patients had type A tympanograms. Otalgia was a delayed symptom significantly associated with increased throat pain. Transient negative middle ear pressure commonly occurs following tonsillectomy.

Response in chronic schizophrenia correlated with chlorpromazine, 7-OH-chlorpromazine and chlorpromazine sulfoxide levels.

The relationship between chlorpromazine, six of its metabolites and therapeutic response in chronic schizophrenic patients was investigated in this study. Logistic regression revealed no correlation between therapeutic response and four metabolites viz. Nor1 chlorpromazine, Nor2 chlorpromazine, chlorpromazine-N-oxide and Nor2 chlorpromazine sulfoxide. A good correlation was seen between CPZ (P = 0.036), 7-hydroxychlorpromazine (P = 0.004), chlorpromazine sulfoxide (P = 0.002) and therapeutic response. Good therapeutic response was correlated to high levels of chlorpromazine and its 7-hydroxy metabolite while high levels of the sulfoxide metabolite appeared to have a negative effect on therapeutic response. Poor responders who had high levels of chlorpromazine also had high levels of the sulfoxide metabolite. This suggests that the difference in response may lie in the difference in the metabolism of the drug.

Important metabolites to measure in pharmacodynamic studies of chlorpromazine.

Plasma concentrations of chlorpromazine (CPZ) and six metabolites were measured in 12 chronic schizophrenic patients on a fixed dose of CPZ. All six metabolites were measured in significant concentrations, ranging from 12 to 57% of the parent drug concentration. They are listed in order of decreasing mean concentration as follows: chlorpromazine-N-oxide > chlorpromazine sulfoxide > 7-OH chlorpromazine > Nor2 chlorpromazine sulfoxide > Nor2 chlorpromazine > Nor1 chlorpromazine. CPZ concentrations showed significant correlation with the 7-OH chlorpromazine metabolite concentration. Since these metabolites have been associated with in vitro activity and occur in significant concentrations, it is recommended that all six metabolites be measured in studies correlating drug levels with pharmacodynamic effects.

Smoking and body weight influence the clearance of chlorpromazine.

The population pharmacokinetic parameters of chlorpromazine (CPZ) in chronic schizophrenic patients were evaluated using 189 plasma concentration measurements from 31 patients. A NONMEM analysis demonstrated that the clearance of CPZ depended on the patient's body weight. Cigarette smoking and cannabis smoking increased the clearance of CPZ. Chronic alcohol consumption and the concurrent use of anticholinergics did not appear to influence the clearance of CPZ significantly.