What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium?

Microalbuminuria is an important risk factor for cardiovascular disease and progressive renal impairment. This holds true in the general population and particularly in those with diabetes, in whom it is common and marks out those likely to develop macrovascular disease and progressive renal impairment. Understanding the pathophysiological mechanisms through which microalbuminuria occurs holds the key to designing therapies to arrest its development and prevent these later manifestations

Apnoea of prematurity - discontinuation of methylxanthines in a resource-limited setting

Background: Methylxanthines such as caffeine have been proven to reduce apnoea of prematurity and are often discontinued at 35 weeks’ corrected gestational age (GA). Objective. To ascertain whether a caffeine protocol based on international guidelines is applicable in our setting, where GA is often uncertain. Methods: A prospective folder review was undertaken of all premature infants discharged home over a 2-month period. Results: Fifty-five babies were included. All babies born at less than 35 weeks’ GA were correctly started on caffeine as per protocol. GA was assigned in 85.5% of cases by Ballard scoring and in 14.5% from antenatal ultrasound findings. Caffeine was discontinued before 35 weeks in 54.5%. Discussion: The main reason for discontinuing caffeine early was the baby’s ability to feed satisfactorily, a demonstration of physiological maturity. As feeding behaviours mature significantly between 33 and 36 weeks, the ability to feed may be a good indication that caffeine therapy can be stopped

Skin microvascular vasodilatory capacity in offspring of two parents with Type 2 diabetes

Aims<br/> Microvascular dysfunction occurs in Type 2 diabetes and in subjects with fasting hyperglycaemia. It is unclear whether this dysfunction relates to dysglycaemia. This study investigated in normogylcaemic individuals whether a genetic predisposition to diabetes, or indices of insulin resistance including endothelial markers, were associated with impaired microvascular function.<br/> Methods<br/> Maximum microvascular hyperaemia to local heating of the skin was measured using laser Doppler flowmetry in 21 normoglycaemic subjects with no family history of diabetes (Group 1) and 21 normoglycaemic age, sex and body mass index-matched offspring of two parents with Type 2 diabetes (Group 2). <br/>Results<br/> Although Group 2 had normal fasting plasma glucose and glucose tolerance tests, the 120-min glucose values were significantly higher at 6.4 (5.3-6.6) mmol/l (median (25th-75th centile)) than the control group at 4.9 (4.6-5.9) mmol/l (P=0.005) and the insulinogenic index was lower at 97.1 (60.9-130.8) vs. 124.0 (97.2-177.7) (P=0.027). Skin maximum microvascular hyperaemia (Group 1: 1.56 (1.39- 1.80) vs. Group 2: 1.53 (1.30-1.98) V, P=0.99) and minimum microvascular resistance which normalizes the hyperaemia data for blood pressure (Group 1: 52.0 (43.2-67.4) vs. Group 2: 56.0 (43.7-69.6) mmHgN, P=0.70) did not differ in the two groups. Significant positive associations occurred between minimum microvascular resistance and indices of the insulin resistance syndrome; plasminogen activator inhibitor type 1 (R-s=0.46, P=0.003), t-PA (R-s=0.36, P=0.03), total cholesterol (R-s=0.35, P=0.02), and triglyceride concentration (R-s=0.35, P=0.02), and an inverse association with insulin sensitivity (R-s=-0.33, P=0.03).<br/> Conclusions<br/> In normoglycaemic adults cutaneous microvascular vasodilatory capacity is associated with features of insulin resistance syndrome, particularly with plasminogen activator inhibitor type 1. A strong family history of Type 2 diabetes alone does not result in impairment in the maximum hyperaemic response

Soil acidity - high rainfall pastures.

Aims of the Project (i) To establish the current pH of the cultivated soils of the high rainfall areas of south-west Western Australia, and the extent to which pH has altered since clearing. (ii) To examine the responsiveness of old land pastures with low current soil pH levels (\u3c 5.5 water) to applied lime. (iii) To relate the responsiveness of subterranean clover-based pastures to measured soil parameters. 80BU14, 81AL10, 81AL12, 81BU18, 81BY18, 81BY25, 81BY26, 82AL4, 82AL5, 82AL55, 82BU7, 82HA35, 82HA36, 82PE1, 82MA20, 83AL7, 83AL9, 83AL10, 83ALll, 83BY29, 84BU9, 84BU10, 84BY37, 84HA21, 84HA37, 84MA21

Soil acidity - high rainfall pastures. Lime on old land pastures - field & glasshouse experiments

Soil Acidity - High Rainfall Pastures (funded by the Australian Meat Research Committee). Lime on old land pastures. 1. Field experiments - 80BU13, 80BU14, 81AL10, 81AL12, 81AL16, 81BU18, 81BY18, 81BY19, 81BY25, 81BY26, 82AL4, 82AL5, 82AL55, 82BU7, 82BU8, 82HA35, 82HA36, 82PE1, 83AL7, 83AL9, 83AL10, 83AL11, 83AL13, 83AL14, 83BU25, 83BU26, 83BY29, 83HA19, 83HA41, 84BU9, 84BY36, 84BY37, 84HA21. 2. Glasshouse experiments - 84GL4. Investigation of factors involved in lime responses on a new land acid peaty sand. 84GL7, 84GL8. Investigation of factors involved in lime responses on old land high rainfall area pastures

Soil acidity - high rainfall pastures

A. Lime on old land pastures. 80BU13, 80BU14, 80BU15, 80BU16, 80BU17, 80BY7, 80BY16, 81AL10, 81AL11, 8IAL12, 81AL13, 81AL14, 81AL15, 81AL16, 81BU18, 81BY15, 81BY16, 81BY17, 81BY18, 81BY19, 81BY24, 81BY25, 81BY16, 81MA12, 81W9, 81Wl0, 81Wll, 82AL2, 82AL3, 82AL4, 82ALS, 82AL6, 82ALSS, 82BU6, 82BU7, 82BU8, 82BY37, 82HA35, 82HA36, 82HA38, 82MA20, 82PE1, 83AL7, 83AL8, 83AL9, 83AL10, 83AL11, 83AL12, 83AL13, 83AL14, 83BU20, 83BU24, 83BU25, 83BU26, 83BY29, 83HA19, 83HA40, 83HA41. B. Lime on new land pastures 82AL7, 82AL8

Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance

Class A serine β-lactamases (SBLs) are key antibiotic resistance determinants in Gram-negative bacteria. SBLs neutralize β-lactams via a hydrolytically labile covalent acyl-enzyme intermediate. Klebsiella pneumoniae carbapenemase (KPC) is a widespread SBL that hydrolyzes carbapenems, the most potent β-lactams; known KPC variants differ in turnover of expanded-spectrum oxyimino-cephalosporins (ESOCs), for example, cefotaxime and ceftazidime. Here, we compare ESOC hydrolysis by the parent enzyme KPC-2 and its clinically observed double variant (P104R/V240G) KPC-4. Kinetic analyses show that KPC-2 hydrolyzes cefotaxime more efficiently than the bulkier ceftazidime, with improved ESOC turnover by KPC-4 resulting from enhanced turnover (k<sub>cat</sub>), rather than altered K<sub>M</sub> values. High-resolution crystal structures of ESOC acyl-enzyme complexes with deacylation-deficient (E166Q) KPC-2 and KPC-4 mutants show that ceftazidime acylation causes rearrangement of three loops; the Ω, 240, and 270 loops, which border the active site. However, these rearrangements are less pronounced in the KPC-4 than the KPC-2 ceftazidime acyl-enzyme and are not observed in the KPC-2:cefotaxime acyl-enzyme. Molecular dynamics simulations of KPC:ceftazidime acyl-enyzmes reveal that the deacylation general base E166, located on the Ω loop, adopts two distinct conformations in KPC-2, either pointing "in" or "out" of the active site; with only the "in" form compatible with deacylation. The "out" conformation was not sampled in the KPC-4 acyl-enzyme, indicating that efficient ESOC breakdown is dependent upon the ordering and conformation of the KPC Ω loop. The results explain how point mutations expand the activity spectrum of the clinically important KPC SBLs to include ESOCs through their effects on the conformational dynamics of the acyl-enzyme intermediate

Symptomatic congenital syphilis in a tertiary neonatal unit in Cape Town, South Africa: High morbidity and mortality in a preventable disease

Background. Despite preventive measures and effective treatment, congenital syphilis continues to impact significantly on neonatal morbidity and mortality. There has been no recent South African (SA) published literature reviewing congenital syphilis, particularly in the context of a tertiary neonatal setting.Objectives. To describe the clinical features of symptomatic neonates with congenital syphilis and to identify modifiable patient, clinical and health facility factors that contributed to syphilis infection.Methods. All positive serological tests for syphilis performed in neonates at Groote Schuur Hospital (GSH), Cape Town, SA, between 1 January 2011 and 31 December 2013 were obtained. Folders were reviewed, and neonates with clinical signs of congenital syphilis were included.Results. Of 50 symptomatic neonates, 19 (38%) died. Twenty-eight mothers (56%) were unbooked and therefore received no antenatal care. Most mothers (98%) were inadequately treated. Health worker-related failures included poor notification and partner tracing as well as failure to recheck syphilis serology after 32 weeks’ gestation in mothers who initially tested negative. Thirty-four neonates required intensive care unit admission. Two significant predictors of mortality were 1-minute and 5-minute Apgar scores <5. Hydrops fetalis was an independent risk factor for mortality, as were moderate to severely abnormal cranial ultrasound scan findings.Conclusions. Congenital syphilis in neonates admitted to the GSH neonatal unit was associated with substantial morbidity and mortality. The modifiable factors identified represent inadequate antenatal healthcare and health system failures. These factors are longstanding, highlighting the need to establish governance and audit processes and address the continuing socioeconomic and sociocultural barriers that mothers face as a way forward in ultimately eliminating this entirely preventable disease.