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Background: Among combat injured, invasive fungal infections (IFIs) result in significant morbidity. Cultures and histopathology are the primary diagnostic methods for IFIs, but they have limitations. We previously evaluated a panfungal polymerase chain reaction assay, which was 83% sensitive and 99% specific for angioinvasive IFIs. Here, we evaluated 3 less resource-intensive seminested assays targeting clinically relevant fungi in the order Mucorales and genera Aspergillus and Fusarium ., Methods: Formalin-fixed paraffin-embedded tissue specimens from a multicenter trauma IFI cohort (2009-2014) were used. Cases were US military personnel injured in Afghanistan with histopathologic IFI evidence. Controls were patients with similar injury patterns and no laboratory IFI evidence (negative culture and histopathology). Seminested assays specific to Mucorales (V4/V5 regions of 18S rDNA), Aspergillus (mitochondrial tRNA), and Fusarium (internal transcribed spacer [ITS]/28A regions of DNA) were compared with a panfungal assay amplifying the internal transcribed spacer 2 region of rDNA and to histopathology., Results: Specimens from 92 injury sites (62 subjects) were compared with control specimens from 117 injuries (101 subjects). We observed substantial agreement between the seminested and panfungal assays overall, especially for the order Mucorales. Moderate agreement was observed at the genus level for Aspergillus and Fusarium . When compared with histopathology, sensitivity and specificity of seminested assays were 67.4% and 96.6%, respectively (sensitivity increased to 91.7% when restricted to sites with angioinvasion)., Conclusions: Prior studies of seminested molecular diagnostics have focused on culture-negative samples from immunocompromised patients. Our findings underscore the utility of the seminested approach in diagnosing soft-tissue IFIs using formalin-fixed paraffin-embedded tissue samples, especially with angioinvasion., Competing Interests: Potential conflicts of interest. The authors have no conflicts to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We conducted a retrospective cohort study that tested 2,000 US military personnel for Coccidioides antibodies in a disease-endemic region. The overall incidence of seroconversion was 0.5 cases/100 person-years; 12.5% of persons who seroconverted had illnesses requiring medical care. No significant association was found between demographic characteristics and seroconversion or disease.

Background: We have previously shown that many chronic, inflammatory diseases are accompanied, and possibly partly caused or exacerbated, by various coagulopathies, manifested as anomalous clots in the form of 'dense matted deposits'. More recently, we have shown that these clots can be amyloid in nature, and that the plasma of healthy controls can be induced to form such clots by the addition of tiny amounts of bacterial lipopolysaccharide or lipoteichoic acid. Type 2 diabetes (T2D) is also accompanied by raised levels of LPS., Methods: We use superresolution and confocal microscopies to investigate the amyloid nature of clots from healthy and T2D individuals., Results: We show here, with the established stain thioflavin T and the novel stains Amytracker™ 480 and 680, that the clotting of plasma from type 2 diabetics is also amyloid in nature, and that this may be prevented by the addition of suitable concentrations of LPS-binding protein., Conclusion: This implies strongly that there is indeed a microbial component to the development of type 2 diabetes, and suggests that LBP might be used as treatment for it and its sequelae.

Osteoporosis is a common, costly and serious disease, which is still too often regarded as an inevitable part of the normal ageing process and therefore sub-optimally treated, especially in the elderly--in fact, only two out of every 10 patients who sustain a hip fracture receive any form of assessment or prophylactic therapy for osteoporosis. One out of five patients die within 1 year after a hip fracture, and < 50% are capable of leading an independent life. Yet very effective anti-fracture therapy, capable of reducing fracture risk by 35 - 60%, is available. A number of publications have recently questioned the safety of drugs routinely used to treat patients with osteoporosis. This paper attempts to put the situation into perspective and expresses the National Osteoporosis Foundation of South Africa's view on the safety of these drugs. Their efficacy in preventing skeletal fractures and their cost-effectiveness are not addressed in any detail. The paper emphasises the fact that all osteoporosis medications have side-effects, some of which are potentially life-threatening.

Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing β cells is still needed. Using a zebrafish model of diabetes, we screened ~7,000 small molecules to identify enhancers of β cell regeneration. The compounds we identified converge on the adenosine signaling pathway and include exogenous agonists and compounds that inhibit degradation of endogenously produced adenosine. The most potent enhancer of β cell regeneration was the adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA), which, acting through the adenosine receptor A2aa, increased β cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating β cell proliferation during regeneration, NECA had only a modest effect during development. The proliferative and glucose-lowering effect of NECA was confirmed in diabetic mice, suggesting an evolutionarily conserved role for adenosine in β cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: To assess the efficacy and safety of adding alogliptin versus uptitrating pioglitazone in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone., Methods: In this randomized, double-blind, active-controlled, parallel-group study, patients with type 2 diabetes and A1c ≥7.0 and ≤10.0% on metformin (≥1500 mg or maximum tolerated dose; Met) and pioglitazone 30 mg (Pio30) received alogliptin 25 mg (Alo25; n = 404) or pioglitazone 15 mg (n = 399) added to Met+Pio30 for 52 weeks. The primary endpoint was change from baseline (CFB) in A1c at weeks 26 and 52, with sequential testing for non-inferiority of Met+Pio30+Alo25 at weeks 26 and 52 and then for superiority at week 52., Results: Met+Pio30+Alo25 showed superior glycaemic control versus Met+Pio45 at week 52 [least squares (LS) mean CFB in A1c, -0.70 vs. -0.29%; p < 0.001]. At week 52, Met+Pio30+Alo25 resulted in greater CFB in A1c regardless of baseline A1c (p < 0.001); higher proportions of patients achieving A1c ≤7.0 (33.2 vs. 21.3%) and ≤6.5% (8.7 vs. 4.3%; p < 0.001); greater CFB in fasting plasma glucose (FPG; LS mean CFB, -0.8 vs. -0.2 mmol/L; p < 0.001); and greater improvements in measures of β-cell function (p < 0.001). Hypoglycaemia incidence was low (Met+Pio30+Alo25, 4.5%; Met+Pio45, 1.5%), mostly mild to moderate, but with two severe events in the Met+Pio30+Alo25 group. No meaningful differences in incidences of individual adverse events were observed between treatments., Conclusions: Adding alogliptin to an existing metformin-pioglitazone regimen provided superior glycaemic control and potentially improved β-cell function versus uptitrating pioglitazone in patients with type 2 diabetes, with no clinically important differences in safety., (© 2011 Blackwell Publishing Ltd.)

Aims: To evaluate the efficacy and safety of alogliptin, a new dipeptidyl peptidase-4 inhibitor, for 26 weeks at once-daily doses of 12.5 and 25 mg in combination with metformin in patients whose HbA(1c) levels were inadequately controlled on metformin alone., Methods and Patients: Patients with type 2 diabetes and inadequate glycaemic control (HbA(1c) 7.0-10.0%) were randomised to continue a stable daily metformin dose regimen (> or = 1500 mg) plus the addition of placebo (n = 104) or alogliptin at once-daily doses of 12.5 (n = 213) or 25 mg (n = 210). HbA(1c), insulin, proinsulin, C-peptide and fasting plasma glucose (FPG) concentrations were determined over a period of 26 weeks., Results: Alogliptin at either dose produced least squares mean (SE) decreases from baseline in HbA(1c) of -0.6 (0.1)% and in FPG of -17.0 (2.5) mg/dl [-1.0 (0.1) mmol/l], decreases that were significantly (p < 0.001) greater than those observed with placebo. The between treatment differences (alogliptin - placebo) in FPG reached statistical significance (p < 0.001) as early as week 1 and persisted for the duration of the study. Overall, adverse events (AEs) observed with alogliptin were not substantially different from those observed with placebo. This includes low event rates for gastrointestinal side effects and hypoglycaemic episodes. There was no dose-related pattern of AE reporting between alogliptin groups and few serious AEs were reported., Conclusion: Alogliptin is an effective and safe treatment for type 2 diabetes when added to metformin for patients not sufficiently controlled on metformin monotherapy.

Asymmetric cell divisions produce all 302 neurons of the C. elegans hermaphrodite. Here, we describe a role for a C. elegans Dishevelled homolog, DSH-2, in an asymmetric neuroblast division. In dsh-2 mutants, neurons normally descended from the anterior neuroblast daughter of the ABpl/rpppa blast cell were frequently duplicated, while non-neuronal cells produced by the posterior daughter cell were often missing. These observations indicate that in the absence of dsh-2 function, the posterior daughter cell was transformed into a second anterior-like cell. Loss of mom-5, a C. elegans frizzled homolog, produced a similar phenotype. We also show that the DSH-2 protein localized to the cell cortex in most cells of the embryo. In the absence of MOM-5/Fz, DSH-2 was localized to the cytoplasm, suggesting that MOM-5 regulates asymmetric cell division by controlling the localization of DSH-2. Although all neurons in C. elegans are produced by an invariant pattern of cell divisions, our results indicate that cell signaling may contribute to asymmetric neuroblast division during embryogenesis.

The Caenorhabditis elegans genome encodes multiple isotypes of alpha-tubulin and beta-tubulin. Roles for a number of these tubulins in neuronal development have been described, but less is known about the isoforms that function during early embryonic development. Microtubules are required for multiple events after fertilization produces a one-cell zygote in C. elegans, including pronuclear migration, mitotic spindle assembly and function, and proper spindle positioning. Here we describe a conditional and dominant mis-sense mutation in the C. elegans alpha-tubulin gene tba-1 that disrupts pronuclear migration and positioning of the first mitotic spindle, and results in a highly penetrant embryonic lethality, at the restrictive temperature of 26 degrees C. Our analysis of the dominant tba-1 (or346ts) allele suggests that TBA-1 assembles into microtubules in early embryonic cells. However, we also show that reduction of tba-1 function using RNA interference results in defects much less severe than those caused by the dominant or346ts mutation, due to partial redundancy of TBA-1 and another alpha-tubulin called TBA-2. Reducing the function of both TBA-1 and TBA-2 results in severe defects in microtubule-dependent processes. We conclude that microtubules in the early C. elegans embryo are composed of both TBA-1 and TBA-2, and that the dominant tba-1(or346ts) mutation disrupts MT assembly or stability. Cell Motil., (Copyright 2004 Wiley-Liss, Inc.)

The mitotic spindle, which partitions replicated chromosomes to daughter cells during cell division, is composed of microtubule assemblies of alpha/beta-tubulin heterodimers. Positioning of the mitotic spindle influences the size and location of daughter cells, and can be important for the proper partitioning of developmental determinants. We describe two semi-dominant mis-sense mutations in tbb-2, one of two C. elegans beta-tubulin genes that are maternally expressed and together are required for microtubule-dependent processes in the early embryo. These mutations result in a posteriorly displaced and misoriented mitotic spindle during the first cell division. In contrast, a probable tbb-2 null allele is recessive, and when homozygous results in less severe spindle positioning defects and only partially penetrant embryonic lethality. Two of the tbb-2 mutations result in reduced levels of TBB-2 protein, and increased levels of a second maternally expressed beta-tubulin, TBB-1. However, levels of TBB-1 are not increased in a tbb-2 mutant with an allele that does not result in reduced levels of TBB-2 protein. We conclude that feedback regulation influences maternal beta-tubulin expression in C. elegans, but cannot fully restore normal microtubule function in the absence of one beta-tubulin isoform.

Using RNA-mediated genetic interference in a phenotypic screen, we identified a conserved nonmuscle myosin II regulatory light chain gene in Caenorhabditis elegans, which we name mlc-4. Maternally supplied mlc-4 function is required for cytokinesis during both meiosis and mitosis and for establishment of anterior-posterior (a-p) asymmetries after fertilization. Reducing the function of mlc-4 or nmy-2, a nonmuscle myosin II gene, also leads to a loss of polarized cytoplasmic flow in the C. elegans zygote, supporting models in which cytoplasmic flow may be required to establish a-p differences. Germline P granule localization at the time of cytoplasmic flow is also lost in these embryos, although P granules do become localized to the posterior pole after the first mitosis. This result suggests that a mechanism other than cytoplasmic flow or mlc-4/nmy-2 activity can generate some a-p asymmetries in the C. elegans zygote. By isolating a deletion allele, we show that removing zygotic mlc-4 function results in an elongation phenotype during embryogenesis. An mlc-4/green fluorescent protein transgene is expressed in lateral rows of hypodermal cells and these cells fail to properly change shape in mlc-4 mutant animals during elongation.

A 48-year-old man with symptoms of presyncope and congestive cardiac failure had hypertrophic cardiomyopathy (HCM) without obstruction. Complete heart block (CHB), a rare complication of this disease, was preceded by complete left bundle-branch block. Right ventricular (RV) heart failure was a dominant clinical feature but improved dramatically after temporary transvenous RV pacing prompting the insertion of a permanent RV inhibited pacemaker. Repeated ventricular fibrillation was successfully controlled by amiodarone. This is the seventh case of HCM complicated by CHB reported in the literature, and the first in which RV endomyocardial biopsies were undertaken. Two other patients reported in the literature had RV inhibited permanent pacemakers implanted, and a further 2 had atrioventricular sequential pacemakers.

Over a period of 4 years Holter monitoring was performed on 607 patients in the Division of Cardiology at Tygerberg Hospital. Indications for monitoring were broadly grouped into four categories: (i) evaluation of symptoms suggestive of disorders of cardiac rhythm (210 patients); (ii) evaluation of arrhythmias associated with a specific underlying cardiac condition (139 patients); (iii) evaluation of a previously documented or suspected arrhythmia (233 patients); and (iv) miscellaneous reasons (25 patients). Findings are presented and aspects of Holter monitoring are discussed. Finally, some recommendations for improving the clinical value of our Holter analyses are made.

Fever patterns associated with pulmonary thromboembolism have not been well characterized. Upon review of 35 consecutive patients with angiographically documented pulmonary emboli, fever was present in 24 patients; and in 20, it was attributed solely to pulmonary thromboembolism. Analysis of these cases indicates that high fever (temperature greater than 39 degrees C) due to pulmonary thromboembolism may occur early, and low-grade fever may continue for a week or more. Fever persisting beyond six days, however, especially with temperatures over 38.5 degrees C, should not be ascribed to pulmonary thromboembolism unless other causes have been carefully excluded. If the clinical setting and patient's findings are consistent with pulmonary thromboembolism, one should not be deterred from presumptively making this diagnosis and initiating therapy because of the presence of high fever.

Using both a 25 mM Lithium di-iodosalicylic acid (LIS) and a 2M NaCl extraction procedure to extract nuclear matrices from white cells we have identified a 0.9 kb nuclear matrix associated region (MAR) in the human pro alpha 2(I) collagen gene. The MAR is located towards the 3' coding end of the gene, it is completely associated with the matrix in transcriptionally inactive white cells but is incompletely associated with the matrix in transcriptionally active fibroblasts. Furthermore the methylation state of the fibroblast gene in the region coinciding with the MAR showed unique differences when compared to adjacent sites in the fibroblast gene and corresponding sites of the white cell gene.

A 32-year-old White man suffered a large transmural inferoposterior myocardial infarction (MI). Coronary vasospasm is strongly suspected of having caused this MI since the ergometrine maleate provocation test gave rise to severe coronary vasospasm resulting in total occlusion of the dominant right coronary artery, without angina or ECG or haemodynamic features of myocardial ischaemia. This is a most unusual response to ergometrine maleate. Possible explanations are suggested and the implications are briefly discussed.