Clinical,biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

Short‐chain enoyl‐CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile‐onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro‐2,3‐dihydroxy‐2‐methylbutyrate and 3‐methylglutaconate (3‐MGC). Increased urine excretion of methacrylyl‐CoA and acryloyl‐CoA related metabolites analyzed by LC‐MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro‐2,3‐dihydroxy‐2‐methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3‐MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh‐like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3‐MGA.     

Breast milk feeding rates of mothers of multiples compared to mothers of singletons.

OBJECTIVE: Over 3% of infants born annually in the United States are from a multiple gestation pregnancy, yet there is little data published about the feeding practices of their mothers. The objectives of this study were to determine and compare the rates of breast milk feeding of mothers of multiples and mothers of singletons. METHODS: Stratified random sampling (n = 686) on the basis of plurality of pregnancy and gestational age at delivery was performed on a 1999 birth certificate database in the greater Cincinnati area. We collected information about infant feeding during the first 6 months of life using a retrospective, self-administered questionnaire and phone interview from mothers of term singletons (TS), preterm singletons (PS), term multiples (TM), and preterm multiples (PM). Data were analyzed using chi-square and logistic or multiple regression. RESULTS: We obtained feeding information from 346 mothers (n = 81 TS, 80 PS, 90 TM, and 95 PM). By 3 days postpartum, PM provided breast milk less often than all other groups: TS = 69%, PS = 66%, TM = 73%, PM = 57% (P =.035). Among mothers who initiated breast milk feeding, the geometric mean duration of at least some breast milk feeding was significantly shorter for PM than for all other groups: TS = 23 weeks, PS = 19 weeks, TM = 24 weeks, and PM = 12 weeks (P =.002). CONCLUSIONS: Further evaluation of the potential causes for the lower breast milk feeding rates among PM is needed to develop effective intervention strategies and increase the number of preterm multiple gestation infants receiving breast milk.     

The expression of human leukocyte antigen-G on trophoblasts abolishes the growth-suppressing effect of interleukin-2 towards them

PROBLEM: We have shown the attenuated human leukocyte antigen (HLA)-G expression on trophoblasts and an aberrant expression of interleukin (IL)-2, a cytotoxic cytokine, in decidual tissue in preeclampsia, where deteriorated trophoblastic invasion into decidual layers may constitute a crucial pathogenesis. We hypothesized that the absence of HLA-G might make trophoblasts susceptible to compromise by IL-2. METHOD OF STUDY: We analyzed the growth of HLA-G-negative and positive cell lines, all of which possessed IL-2 receptors, in the culture with or without IL-2 supplementation. RESULTS: The proliferation of HLA-G positive trophoblastic cell lines (BeWo and JEG-3) was not influenced by the addition of IL-2, whereas a HLA-G-negative trophoblastic cell line (JAR) exhibited significantly decreased proliferation when cultured with IL-2. Interestingly, the transfection of JAR cells with HLA-G completely eliminates the growth-inhibitory effect of IL-2. CONCLUSION: The expression of HLA-G may commit trophoblasts to evade cell damage by IL-2, which may be relevant to maternal tolerance of the fetus during pregnancy and its derangement as exemplified by preeclampsia.     

HLA-G in reproduction: studies on the maternal-fetal interface

For more than a decade, investigators have known that membrane-bound and soluble isoforms of the HLA class Ib molecule, HLA-G, are present at the maternal-fetal interface. Although it is clear that extravillous cytotrophoblast cells are major producers, other cells may also contribute. Recent studies in our laboratory raised the question of whether soluble isoforms might reach the maternal and/or fetal blood circulation. A capture enzyme-linked immunoabsorbent assay (ELISA) identified soluble HLA-G (sHLA-G) in maternal blood throughout pregnancy but failed to detect sHLA-G in cord sera. Further studies suggested that the circulating proteins may be either free heavy chain (sHLA-G1 and/or sHLA-G2) or exclusively sHLA-G2. To study the potential function(s) of the soluble isoforms to modulate local or systemic immunity in mothers, we generated recombinant sHLA-G1 and -G2 in both prokaryotic and eukaryotic systems. Preliminary experiments conducted using DNA microarray analysis suggest that sHLA-G is capable of modulating gene expression in blood mononuclear leukocytes. Potential local targets were also identified; decidual and placental macrophages but not trophoblast cells contained mRNA encoding two of the known receptors for HLA-G, ILT2 and ILT4. Collectively, the studies are consistent with the hypothesis that sHLA-G produced at the maternal-fetal interface targets to the cells of the monocyte/macrophage lineage and modulates their functions for the benefit of pregnancy.     

Tumor vascular signals in renal masses: detection with Doppler US

The vascularity of 49 renal masses (26 malignant and 23 benign lesions) was investigated with duplex Doppler ultrasound. Doppler signals obtained at the margins of renal masses were defined as "tumor signals" when the Doppler-shifted frequency of the lesion exceeded the frequency shift in the ipsilateral main renal artery. These exceeded 2.5 kHz with a 3-MHz insonating frequency. Among the 26 renal masses that subsequently proved to be malignant, tumor signals were obtained in 15 of 18 (83%) untreated renal cell carcinomas, in three of four Wilms tumors, and in two patients with metastases to the kidney, but not in the one patient with lymphoma. None of the 23 benign renal masses demonstrated tumor signals. Tumor vascularity in malignant lesions gives rise to abnormal, high-velocity, Doppler-shifted signals that can help in the differential diagnosis of renal masses.     

Peribursal fat plane of the shoulder: anatomic study and clinical experience

A comprehensive anatomic and radiographic analysis of the peribursal fat plane in 12 cadavers confirmed that the fat plane seen on radiographs represents extrasynovial fat lining the subacromial bursa and documented the anatomic relations of the bursa. A three-part retrospective clinical evaluation of rotator cuff tears, calcific tendinitis, and rheumatoid arthritis was performed. Two osteoradiologists blindly graded the appearance of the peribursal fat plane with the shoulder in external versus internal rotation in 21 patients with arthrographically intact rotator cuffs and 21 patients with disrupted rotator cuffs. The peribursal fat plane was seen better with disrupted rotator cuffs. The peribursal fat plane was seen better with the shoulder in internal rotation and was seen in 60% of control subjects but only 21% of patients with rotator cuff tears. Partial or complete obliteration of this fat plane is a sensitive (79%) but less specific (60%) indicator of rotator cuff tears. Obliteration of the peribursal fat plane by inflammatory processes in adjacent tissues, including calcific tendinitis and rheumatoid arthritis, occurred with a high frequency.     

Comparison of digital systems and conventional dental film for the detection of approximal enamel caries

Objectives

The aims of this study were (1) to compare the accuracy of the detection of approximal enamel caries lesions using three intraoral storage phosphor plate digital systems and one conventional film-based radiographic system; and (2) to determine whether there is a correlation between the histological and radiographic measurements of enamel caries.

Methods

160 approximal surfaces were radiographed under standardized conditions using three storage phosphor stimulable systems (DenOptix and Digora FMX with white and blue plates), and one film system (Insight film). 17 observers scored the images for the presence and depth of caries using a 4-point scale. The presence of caries was validated histologically (gold standard). Two-way analysis of variance was used to test the differences in sensitivity, specificity and overall accuracy (TP + TN). The data from the radiographic and histological measurements were statistically analysed by Spearman’s rank correlation coefficient.

Results

Two-way analysis of variance and the post hoc t-test demonstrated that Digora (white plate) had higher specificity and overall accuracy values than DenOptix (P = 0.021); there was no statistically significant difference among the other imaging modalities (P > 0.05). There was no significant correlation between the histological depth measurements and the radiographic measurements from Digora (blue plate) (P = 0.43), Digora (white plate) (P = 0.15), DenOptix (P = 0.17) and Insight film (P = 0.06).

Conclusions

The results suggest that (1) the performance of the three storage phosphor image plate systems was similar to that of the Insight film for detection of approximal enamel caries, and (2) the increase in histological depth of enamel caries was not significantly correlated with radiographic measurements.     

Overt ischemic colitis after endovascular repair of aortoiliac aneurysms

OBJECTIVE: Controversy exists as to the cause of ischemic colitis complicating endovascular aneurysm repair. Occlusion of the hypogastric arteries (HAs) during endovascular repair of aortoiliac aneurysms (AIAs) results in a significant incidence of buttock claudication, and has been suggested as a causative factor in the development of postprocedural colonic ischemia, in addition to factors such as systemic hypotension, embolization of atheromatous debris, and interruption of inferior mesenteric artery inflow. To analyze the relationship between perioperative HA occlusion and postoperative ischemic colitis, we reviewed our experience over 2 years with Food and Drug Administration-approved endovascular graft devices for treatment of AIAs. METHODS: Elective repair of AIAs with bifurcated endovascular grafts was performed in 233 patients over a 2-year period. These included 184 AneuRx grafts, 17 Ancure grafts, and 32 Excluder grafts. During the experience, 44 patients (18.9%) underwent unilateral perioperative HA occlusion (28 right, 16 left) during the course of endovascular AIA repair, and 1 patient (0.4%) underwent bilateral HA occlusion. RESULTS: In 4 patients (1.7%) signs and symptoms of ischemic colitis developed 2.0 +/- 1.4 days postoperatively. In all patients the diagnosis was confirmed at sigmoidoscopy, and initial treatment included bowel rest, hydration, and intravenous antibiotic agents. Three patients with bilateral patent HAs required colonic resection 14.7 +/- 9.7 days after the initial diagnosis, and 2 of these 3 patients died in the postoperative period. Pathologic findings confirmed the presence of atheroemboli in the colonic vasculature in all 3 patients who underwent colonic resection. The fourth patient had undergone multiple manipulations of the left HA in an unsuccessful attempt to preserve patency of this vessel during AIA repair. This patient recovered completely with nonoperative management. Perioperative unilateral HA occlusion was not associated with a significantly higher incidence of postoperative ischemic colitis. CONCLUSION: Perioperative HA occlusion during aortoiliac open or endovascular surgery may contribute to development of the rare but potentially lethal complication of ischemic colitis. However, our extensive experience suggests that embolization of atheromatous debris to the HA tissue beds during endovascular manipulations, rather than proximal HA occlusion, is the primary cause of clinically significant ischemic colitis after endovascular aneurysm repair.