In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis

Amyloid diseases encompass >20 medical disorders that include amyloid protein A (AA) amyloidosis, Alzheimer's disease, and type 2 diabetes. A common feature of these conditions is the selective organ deposition of disease-specific fibrillar proteins, along with the sulfated glycosaminoglycan, heparan sulfate. We have generated transgenic mice that overexpress human heparanase and have tested their susceptibility to amyloid induction. Drastic shortening of heparan sulfate chains was observed in heparanase-overproducing organs, such as liver and kidney. These sites selectively escaped amyloid deposition on experimental induction of inflammation-associated AA amyloidosis, as verified by lack of material staining with Congo Red, as well as lack of associated polysaccharide, whereas the same tissues from control animals were heavily infiltrated with amyloid. By contrast, the spleens of transgenic mice that failed to significantly overexpress heparanase contained heparan sulfate chains similar in size to those of control spleen and remained susceptible to amyloid deposition. Our findings provide direct in vivo evidence that heparan sulfate is essential for the development of amyloid disease.     

Pregnancy outcome in congenital dyserythropoietic anemia type I

Objectives: Congenital dyserythropoietic anemia type I (CDA I) is a rare inherited disease characterized by moderate to severe macrocytic anemia and abnormal erythroid precursors with nuclear chromatin bridges and spongy heterochromatin. Moderate to severe maternal anemia is a recognized independent risk factor for low birth weight (LBW) and complicated delivery. The aim of the study was to review the outcome of pregnancies in women with CDA I. Methods: The clinical and laboratory records of 28 spontaneous pregnancies in six Bedouin women with CDA I were reviewed. The results were compared with findings from a retrospective review of a large population‐based registry including all pregnancies in Bedouin women during the same 15‐yr period. Results: Eighteen pregnancies in women with CDA I (64%) were complicated. One pregnancy was aborted spontaneously in the first trimester and one resulted in a non‐viable fetus (stillborn at 26 wk). Cesarean section (CS) was performed in 10 pregnancies (36%). Eleven of the 26 newborns (42%) had a LBW: six were born prematurely and five were small for gestational age. The odds ratio for CS in women with CDA I compared with healthy Bedouin women was 4.5 [95% confidence interval (CI) 1.2–10.3], and for a LBW infant, 5.5 (95% CI 2.4–12.3). Careful follow‐up was associated with significantly better fetal outcome (P = 0.05). Conclusions: Pregnancies in women with CDA I are at high risk for delivery‐related and outcome complications. To improve fetal outcome, women with CDA I should be carefully monitored during pregnancy.     

Predicting In-Hospital Mortality at Admission to the Medical Ward: A Big-Data Machine Learning Model

BackgroundGeneral medical wards admit high-risk patients. Artificial intelligence algorithms can use big data for developing models to assess patients’ risk stratification. The aim of this study was to develop a mortality prediction machine learning model using data available at the time of admission to the medical ward.MethodsWe included consecutive patients (ages 18-100) admitted to medical wards at a single medical center (January 1, 2013-December 31, 2018). We constructed a machine learning model using patient characteristics, comorbidities, laboratory tests, and patients’ emergency department (ED) management. The model was trained on data from the years 2013 to 2017 and validated on data from the year 2018. The area under the curve (AUC) for mortality prediction was used as an outcome metric. Youden index was used to find an optimal sensitivity-specificity cutoff point.ResultsOf the 118,262 patients admitted to the medical ward, 6311 died (5.3%). The single variables with the highest AUCs were medications administered in the ED (AUC = 0.74), ED diagnosis (AUC = 0.74), and albumin (AUC = 0.73). The machine learning model yielded an AUC of 0.924 (95% confidence interval [CI]: 0.917-0.930). For Youden index, a sensitivity of 0.88 (95% CI: 0.86-0.89) and specificity of 0.83 (95% CI: 0.83–0.83) were observed. This corresponds to a false-positive rate of 1:5.9 and negative predictive value of 0.99.ConclusionA machine learning model outperforms single variables predictions of in-hospital mortality at the time of admission to the medical ward. Such a decision support tool has the potential to augment clinical decision-making regarding level of care needed for admitted patients.     

Molecular Imaging of Membrane Transporters’ Activity in Cancer: a Picture is Worth a Thousand Tubes

Molecular imaging allows the non-invasive assessment of membrane transporter expression and function in living subjects. Such technologies have the potential to become diagnostic and prognostic tools, allowing detection, localization, and prediction of response of tumors and their metastases to therapy. Beyond tumors, imaging can also help understand the role of transporters in adverse drug effects and drug clearance. Here, we review molecular imaging technologies that monitor transporter-mediated processes. We emphasize emerging probe substrates and potential clinical applications of imaging the function of membrane transporters in cancer.KEY WORDS: membrane transporters, molecular imaging, multidrug resistance, near infrared, optical imaging     

Limited surgical resection for graft salvage following recovery from complicated exfoliative rejection in pediatric intestinal recipients

Complications of ER contribute significantly to morbidity and mortality following intestinal transplantation. The surgical management of three pediatric patients who experienced complications of late ER after composite LSB transplantation is described, highlighting the potential for allograft salvage after limited surgical resection. A retrospective case series was compiled. Data collected included time to ER from transplant, medical management of ER, complications, and surgical management of ER complications. All patients had undergone composite LSB transplantation between one and two yr of age. Time to ER after transplantation was 9.5–26.5 months. ER complications included ileal allograft stricture, intramural hematoma with perforation of jejunal allograft, and massive GI hemorrhage secondary to focal ulceration and pseudopolyp formation. With evidence of mucosal regeneration, all three patients underwent limited segmental allograft resection. Two patients continue to maintain satisfactory allograft function 39–44 months following operation. The third patient retained adequate allograft function until he developed PTLD, subsequently dying from disseminated Adenovirus infection 51 months after resection. Severe disruption of intestinal allograft integrity in ER can lend itself to medically refractory complications. Prompt recognition and surgical correction of complications can play a crucial role in allograft salvage and patient survival after ER.     

No association between histo-blood group antigens and susceptibility to clinical infections with genogroup II norovirus

Noroviruses (NoVs) are a leading cause of viral gastroenteritis in humans. In the present study, the association between NoV susceptibility and the ABO histo-blood group was studied during 2 outbreaks of acute gastroenteritis in military units in Israel caused by genogroup II (GII) NoVs. The findings demonstrate that, unlike for genogroup I of NoV, there is no association between the ABO histo-blood group and clinical infection with GII NoVs. This is the largest study to test the association between NoVs, proven clinical infection with GII, and the ABO histo-blood group.     

Varicella zoster infection and pulmonary complications

A 34-year-old immunocompetent man with varicella zoster (VZ) infection developed deep vein thrombosis and pulmonary embolism after suffering severe pneumonitis. He recovered after treatment with acyclovir, high-dose steroids, and ventilatory support. The endothelial damage could be a direct link between VZ pneumonitis and pulmonary emboli.     

A case of μ heavy-chain disease associated with hyperglobulinemia, anemia, and a positive Coombs test

 We report here for the first time a patient with μ heavy-chain disease (HCD), hyperimmunoglobulinemia, and a positive direct antiglobulin test (DAT, Coombs test). The heavy-chain diseases involve the proliferation of lymphoplasma cells of B cell origin and are characterized by the production of incomplete heavy chains devoid of light chains. The association of μ heavy-chain disease with either hyperglobulinemia or a positive DAT has not been reported in the literature to date. In this patient, immunofixation of serum proteins with monospecific antisera to α-, γ-, μ,- or δ-chains and to κ- and λ-chains revealed a precipitation band with antibody to IgM, but not with κ and λ light-chain antibodies, indicating μ heavy-chain disease. Hyperglobulinemia was present, which is very uncommon for HCD. A DAT of the patient's red blood cells (RBC) was found to be strongly positive for anti-IgG but negative for anti-IgM, -IgA, -C3c, and -C3d. However, when the eluate from the patient's red blood cells was investigated with nephelometry, it was found to contain antigens reactive with anti-γ as well with anti-μ-antiserum. When a DAT was performed with a randomly chosen test cell incubated with the eluate, the antibody-containing eluate was shown to react with anti-IgG as well as with anti-IgM-antiserum. In summary, the eluate from the patient's RBCs contained IgG and an immunoglobulin structure reactive with anti-IgM in an RBC agglutination assay as well as with anti-μ antiserum in a nephelometric investigation. Whether this IgM on the patient's erythrocytes is penta- or oligomeric, complete IgM, or the heavy chain cannot be concluded from these observations. Received: May 15, 1998 / Accepted: August 24, 1998     

Maternal medical compromise during pregnancy and pregnancy outcomes

Objective: To examine the outcomes of pregnancy and newborn following an event of maternal medical compromise during pregnancy.

Methods: A retrospective study was performed on all patients hospitalized following an event of medical compromise during pregnancy. Medical compromise was divided to acute or chronic bleeding, major or complicated operations, and admission to intensive care unit (ICU). Data collected included maternal, fetal, neonatal and child’s follow-up.

Results: The study included 51 pregnant patients and 58 fetuses. The study group had increased risk of preterm deliveries (35.0 versus 6.5%, p?p?p?=?0.002). Patients with acute bleeding had higher rates of cesarean sections, preterm deliveries, admissions to neonatal ICU and neonatal mortality. Two cases of fetal abnormalities included brain abnormalities and pericardial effusion. Three terminations of pregnancies were performed: two in patients in ICU due to severe maternal medical condition and one in the fetus with brain abnormalities.

Conclusions: Maternal medical compromise during pregnancy increases the risk for preterm deliveries, cesarean delivery and low Apgar scores. Acute bleeding was the main cause of medical compromised and with the higher rates of adverse outcomes.