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Several mechanisms are implicated in the pathogenesis of diabetic retinopathy. They include biochemical, hemodynamic, and hormonal factors, all of which have an important role in the development of diabetic retinopathy. These factors are not independent of each other, but rather they interact and together are responsible for the well-known lesions of vascular occlusion, microaneurysms, hemorrhages' hard exudates, and eventually new vessel formation.

Vinod Patel and colleagues evaluate the sensitivity and specificity of quantitative PCR using Xpert MTB/RIF for diagnosis of TB meningitis in the high-burden setting of South Africa. Please see later in the article for the Editors' Summary

The determinants of Xpert MTB/RIF sensitivity, a widely used PCR test for the diagnosis of tuberculosis (TB) are poorly understood. We compared culture time-to-positivity (TTP; a surrogate of bacterial load), MTB/RIF TB-specific and internal positive control (IPC)-specific CT values, and clinical characteristics in patients with suspected TB who provided expectorated (n = 438) or induced sputum (n = 128), tracheal aspirates (n = 71), bronchoalveolar lavage fluid (n = 152), pleural fluid (n = 76), cerebral spinal fluid (CSF; n = 152), pericardial fluid (n = 131), or urine (n = 173) specimens. Median bacterial load (TTP in days) was the strongest associate of MTB/RIF positivity in each fluid. TTP correlated with CT values in pulmonary specimens but not extrapulmonary specimens (Spearman's coefficient 0.5043 versus 0.1437; p = 0.030). Inhibition affected a greater proportion of pulmonary specimens than extrapulmonary specimens (IPC CT > 34: 6% (47/731) versus 1% (4/381; p < 0.0001). Pulmonary specimens had greater load than extrapulmonary specimens [TTPs (interquartile range) of 11 (7–16) versus 22 (18–33.5) days; p < 0.0001]. HIV-infection was associated with a decreased likelihood of MTB/RIF-positivity in pulmonary specimens but an increased likelihood in extrapulmonary specimens. Mycobacterial load, which displays significant variation across different body compartments, is the main determinant of MTB/RIF-positivity rather than PCR inhibition. MTB/RIF CT is a poor surrogate of load in extrapulmonary specimens.

SUMMARYSince the retinal vessels have no sympathetic innervation, blood flow in response to raised blood pressure is dependent on autoregulation. To determine the effect of hypertension on retinal haemodynamics and the autoregulatory capacity of the retinal circulation under conditions of normoglycaemia and hyperglycaemia, retinal blood flow was measured before and after raising the systemic blood pressure in ten normal control subjects, ten diabetic subjects with blood glucose < 10 mmol 11 and ten diabetic subjects with blood glucose > 15 mmol 1-'. A controlled nse in systemic blood pressure was achieved using an intravenous infusion of tyramine. Retinal volume flow was determined from red cell velocity using laser Doppler velocimetry and from retinal vessel diameter measurements using digital image analysis of fundus photographs. With a 40 % increase in mean arterial blood pressure (MAP), there was a significant increase in retinal blood flow of 32.9 + 7-1 % in non-diabetic controls. In diabetics at the low blood glucose level, the increase in retinal blood flow was significant at 30% increase in MAP (23.6 + 87 %, P = 0-032) and at 40 % increase (49-9 + 12-03 %, P = 0-004). Diabetics with high blood glucose failed to autoregulate at any of the increased levels of MAP (15 % increase, 27 0 + 11 1 %; 30 % increase, 66.9 + 19.8 %; and 40 % increase, 101 9 + 21 4 %; P < 0.022). The coefficients of autoregulation showed that in non-diabetic controls, retinal vascular autoregulation broke down with increases in MAP of between 30 and 40 %. In diabetic subjects, it broke down between 15 and 30 % in normoglycaemia and at less than 15 % in hyperglycaemia. This study demonstrates an impairment in retinal vascular autoregulation in response to raised systemic blood pressure in diabetic subjects, more so at an elevated blood glucose level, thus providing a mechanism for the detrimental effect of hypertension on diabetic retinopathy.

Rationale: Current tools for the rapid diagnosis of tuberculous meningitis (TBM) are suboptimal. We evaluated the clinical utility of a quantitative RD-1 IFN-g T-cell enzyme-linked immunospot (ELISPOT) assay (T-SPOT.TB), using cerebrospinal fluid cells for the rapid immunodiagnosis of TBM. Objectives: To evaluate the diagnostic utility of the RD1 antigenspecific ELISPOT assay for the diagnosis of tuberculous meningitis. Methods: The ELISPOT assay was evaluated in 150 patients with suspected TBM who were categorized as definite-TBM, probable-TBM, and non-TBM. Culture or polymerase chain reaction positivity for Mycobacerium tuberculosis served as the reference standard. To determine the diagnostic value of the ELISPOT assay, a clinical prediction rule was derived from baseline clinical and laboratory parameters using a multivariable regression model. Measurements and Main Results: A total of 140 patients (81% HIVinfected; median CD4 count, 160 cells/mm 3 ) were included in the final analysis. When comparing the definite-TBM (n 5 38) and non-TBM groups (n 5 48), the ELISPOT assay (cut point of >228 spot-forming cells per 1 million mononuclear cells) was a useful rule-in test: sensitivity 58% (95% confidence interval [CI], 41-74); specificity 94% (95% CI, 83-99). However, ELISPOT outcomes improved when other rapid tests were concurrently used to exclude bacterial (Gram stain) and cryptococcal meningitis (latex-agglutination test) within the non-TBM group. Using this approach, the ELISPOT assay (cut point of >46 spot-forming cells) was an excellent rule-in test: sensitivity 82% (95% CI, 66-92); specificity 100% (95% CI, 78-100); positive predictive value, 100% (95% CI, 89-100); negative predictive value, 68% (95% CI, 45-86); area under the curve, 0.90. The ELISPOT assay had incremental diagnostic value compared with the clinical prediction rule. Conclusions: The RD-1 ELISPOT assay, using cerebrospinal fluid mononuclear cells and in conjunction with other rapid confirmatory tests (Gram stain and cryptococcal latex-agglutination test), is an accurate rapid rule-in test for TBM in a TB and HIV endemic setting.

Background: To evaluate vitamin B12 and folate status in pregnancy and their relationship with maternal obesity, gestational diabetes mellitus (GDM), and offspring birthweight. Methods: A retrospective case-control study of 344 women (143 GDM, 201 no-GDM) attending a district general hospital and that had B12 and folate levels measured in the early 3rd trimester was performed. Maternal history including early pregnancy body mass index (BMI) and neonatal data (birthweight, sex, and gestational age) was recorded for all subjects. Results: 26% of the cohort had B12 levels <150 pmol/L (32% vs. 22% in the two groups respectively, p < 0.05) while 1.5% were folate deficient. After adjusting for confounders, 1st trimester BMI was negatively associated with 3rd trimester B12 levels. Women with B12 insufficiency had higher odds of obesity and GDM (aOR (95% CI) 2.40 (1.31, 4.40), p = 0.004, and 2.59 (1.35, 4.98), p = 0.004, respectively), although the latter was partly mediated by BMI. In women without GDM, the lowest quartile of B12 and highest quartile of folate had significantly higher adjusted risk of fetal macrosomia (RR 5.3 (1.26, 21.91), p = 0.02 and 4.99 (1.15, 21.62), p = 0.03 respectively). Conclusion: This is the first study from the UK to show that maternal B12 levels are associated with BMI, risk of GDM, and additionally may have an independent effect on macrosomia. Due to the increasing burden of maternal obesity and GDM, longitudinal studies with B12 measurements in early pregnancy are needed to explore this link.