A Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside

The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician’s observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.     

Distribution and spatial geometry of dopamine interplexiform cells in the retina. II. External arborizations in the adult rat and monkey

The morphology and distribution of dopaminergic interplexiform cells in adult rat and monkey retinas were analyzed to determine any correlation with the function of dopamine in the outer retinal layers. The retinas were processed as whole mounts for tyrosine hydroxylase immunohistochemistry. There was a network formed by the sclerally directed processes of interplexiform cells in the inner nuclear, outer plexiform, and outer nuclear layers running throughout the retina. Their density was higher in the superior retina than in the inferior retina of the rat and was especially high in the superior temporal quadrant. The external network in this quadrant was significantly less dense in the monkey than in the rat, as are the interplexiform cells. The somata of interplexiform and other dopaminergic cells were about the same size in both rats and monkeys. Computer-assisted reconstruction of external arborizations of individual cells showed that external processes lay very close to horizontal and photoreceptor cells and also to blood capillaries. Because they were long, thin, and highly varicose; branched at right angles; and often arose from an axon hillock, the external processes were identified as axons. Therefore, we define the dopaminergic interplexiform cells as multiaxonal neurons, with at least one outwardly directed axon that reaches the outer plexiform layer. The function of the network of external processes from the interplexiform dopaminergic cells is discussed in terms of modulating the release of dopamine to external layers.     

Differential effect of in vitro degradation on resin-dentin bonds produced by self-etch versus total-etch adhesives

OBJECTIVE: To evaluate the effect of an in vitro challenge (NaOCl immersion) on microtensile bond strength (MTBS) of five adhesive systems to dentin. METHODS: Flat dentin surfaces from 40 molars were bonded with three total-etch adhesives (Single Bond, Prime&Bond NT and the experimental Prime&Bond XP), and two self-etching agents (Clearfil SE Bond and Etch&Prime 3.0). Composite build-ups were constructed with Tetric Ceram. Teeth were then sectioned into beams of 1.0 mm2 cross-sectional area. Half of the beams were immersed in 10% NaOCl aqueous solution for 5 h. Each beam was tested in tension in an Instron machine at 0.5 mm/min. Data were analyzed by 2-way ANOVA and multiple comparisons tests (p < 0.05). RESULTS: Clearfil SE Bond and Single Bond attained higher MTBS than the other three adhesives. Prime&Bond NT and Prime&Bond XP performed equally, and Etch&Prime resulted in the lowest MTBS. After NaOCl immersion, MTBS decreased in all groups. The highest MTBS values were obtained for Clearfil SE Bond and Prime&Bond XP. Scaning electron microscopy observation of debonded sticks evidenced dissolution and microstructural alterations of intertubular dentin, except when Clearfil SE Bond was used. CONCLUSIONS: Resin-dentin bonds are prone to chemical degradation. The extent of the resin degradation is adhesive system specific. Chemical degradation of the nonresin infiltrated collagen fibers does also exist in total-etch adhesives. Both processes may reduce long-term resin-dentin bond strength.     

A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia‐inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

A comparative study of serological tests and PCR for the diagnosis of equine piroplasmosis

A total of 105 serum samples from endurance horses from different stables in Dubai were examined for the presence of antibodies against Theileria equi and Babesia caballi using immunofluorescence antibody test (IFAT) and competitive enzyme-linked immunosorbent assay (cELISA). A TaqMan real-time polymerase chain reaction (PCR) was used to detect DNA of piroplasms in specimens of clotted blood or EDTA blood samples of the same animals. Out of the 105 serum samples, the IFAT detected antibodies against T. equi in 35 (33.3%) cases while the cELISA gave 34 (32.4%) positive results. Eleven (10.5%) of the 105 sera were positive in the B. caballi IFAT while an additional five (4.8%) other specimens were diagnosed positive using the cELISA. The serological results showed that 13 (12.4%) horses had antibodies against both T. equi and B. caballi. The TaqMan real-time PCR detected DNA of piroplams in 33 (31.4%) samples while serological methods found antibodies in 38 (36.2%) horses.     

Neonatal hyperglycemia alters the neurochemical profile,dendritic arborization and gene expression in the developing rat hippocampus

Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long‐term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate‐HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe‐HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo ¹H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule‐associated protein (MAP)‐2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe‐HG group, compared with the control group (p < 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP‐2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu‐Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long‐term hippocampus‐mediated cognitive deficits in human ELGANs.