The Wnt/β-catenin pathway determines the predisposition and efficiency of liver-to-pancreas reprogramming.

Unlabelled: Transdifferentiation (TD) is the direct reprogramming of adult cells into cells of alternate fate and function. We have previously shown that liver cells can be transdifferentiated into beta-like, insulin-producing cells through ectopic expression of pancreatic transcription factors (pTFs). However, the efficiency of the process was consistently limited to <15% of the human liver cells treated in culture.

LMOD3-Associated Nemaline Myopathy: Prenatal Ultrasonographic, Pathologic, and Molecular Findings.

To describe the prenatal presentation, including ultrasonographic, histologic, and molecular findings, in 2 fetuses affected with LMOD3-related nemaline myopathy. Prenatal ultrasonographic examinations and histopathologic studies were performed on 2 fetuses with evidence of nemaline myopathy. To establish a molecular diagnosis, whole-exome sequencing was pursued for the affected fetuses.

Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.

We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome (CNS) diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case. Using exome sequencing and targeted Sanger sequencing, two homozygous truncating mutations, c.1513C>T (p.

Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone-mediated tubulinopathy.

Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/β-tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging.

[RARE DISEASES DTC: DIAGNOSIS, TREATMENT AND CARE].

Rare diseases are chronic, progressive genetic disorders, which affect around 6-8% of the general population, mainly children. Therefore, in Israel approximately 500,000 people are probably affected by a rare disease. In this article, we review some of the issues pertaining to rare diseases, such as the need for accurate diagnosis which is necessary not only for specific care and treatment but also for informed family planning.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein.

Cell-based therapy approaches: the hope for incurable diseases.

Cell therapies aim to repair the mechanisms underlying disease initiation and progression, achieved through trophic effect or by cell replacement. Multiple cell types can be utilized in such therapies, including stem, progenitor or primary cells. This review covers the current state of cell therapies designed for the prominent disorders, including cardiovascular, neurological (Parkinson's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury), autoimmune (Type 1 diabetes, multiple sclerosis, Crohn's disease), ophthalmologic, renal, liver and skeletal (osteoarthritis) diseases.

Retinal blood flow velocity in patients with age-related macular degeneration.

Purpose/aim Of The Study: To study changes in retinal blood flow velocity in patients with early and neovascular age-related macular degeneration (AMD). We used the Retinal Function Imager (RFI, Optical Imaging Ltd., Rehovot, Israel), a noninvasive diagnostic approach for measuring blood flow velocity.

The correlation between retinal blood flow velocity measured by the retinal function imager and various physiological parameters.

Background And Objective: The retinal function imager (RFI) (Optical Imaging Ltd., Rehovot, Israel) measures retinal blood flow velocity non-invasively. The authors studied the reproducibility of these measurements and assessed the effect of physiological components on them.

The effect of intravitreal bevacizumab (Avastin) injection on retinal blood flow velocity in patients with choroidal neovascularization.

Purpose: To study the short-term effects of intravitreal bevacizumab (Avastin) on retinal blood flow velocity and compare them to clinical outcomes assessed by optical coherence tomography (OCT) and tests of visual acuity.

Methods: The Retinal Function Imager (RFI) was used noninvasively and quantitatively to measure retinal blood flow velocity. Eight patients receiving intravitreal injection of Avastin for choroidal neovascularization (CNV) were included in this study.

High-resolution wide-field imaging of perfused capillaries without the use of contrast agent.

Purpose: Assessment of capillary abnormalities facilitates early diagnosis, treatment, and follow-up of common retinal pathologies. Injected contrast agents like fluorescein are widely used to image retinal capillaries, but this highly effective procedure has a few disadvantages, such as untoward side effects, inconvenience of injection, and brevity of the time window for clear visualization. The retinal function imager (RFI) is a tool for monitoring retinal functions, such as blood velocity and oximetry, based on intrinsic signals.

Increased retinal blood flow velocity in patients with early diabetes mellitus.

Purpose: To compare retinal blood flow velocity in small vessels of patients with early diabetes mellitus (DM), without any morphologic changes related to diabetic retinopathy, with that in a control group.

Methods: The authors used the retinal function imager to measure blood flow velocities, from many small vessels, simultaneously. Twenty-three eyes of 14 patients with early DM and 51 eyes of 31 healthy subjects were enrolled.

Retinal blood flow velocity measured by retinal function imaging in retinitis pigmentosa.

Background: To measure the retinal blood flow velocity in patients with retinitis pigmentosa using the retinal function imaging technique.

Methods: The clinical observational investigation included a study group of five eyes of five patients (age: 55.7 ± 8.

Liposomes for HIV prophylaxis.

There are approximately 33.4 million adults living with HIV worldwide of which an estimated 15.7 million are women.

Central serous chorioretinopathy shows reduced retinal flow circulation in retinal function imaging (RFI).

Purpose: To assess retinal blood flow in patients with central serous chorioretinopathy (CSR).

Methods: The hospital-based observational comparative study included a study group with 12 patients (age: 45 ± 13 years) with an acute onset of CSR and a control group of 12 subjects matched for age and gender with the study group. The diagnosis was substantiated by fluorescein angiography and optical coherence tomography.

Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and is considered to be the outcome of chronic liver inflammation. Currently, the main treatment for HCC is surgical resection. However, survival rates are suboptimal partially because of tumor recurrence in the remaining liver.

Toll-like receptor 3 signaling attenuates liver regeneration.

Unlabelled: The current model for liver regeneration suggests that cell damage triggers Toll-like receptor (TLR) signaling via MyD88, leading to the induction of nuclear factor kappaB (NF-kappaB) and secretion of inflammatory cytokines that in turn prime liver regeneration. TLR3 is unique among TLRs in that it signals through TRIF (TIR domain-containing adaptor-inducing interferon-beta), not through MyD88, and may lead to activation of either the inflammatory or apoptotic pathway. The inflammatory pathway leads to NF-kappaB activation, whereas the apoptotic pathway, believed to be mediated by Rip3, leads to caspase-8 activation.

Functional magnetic resonance imaging monitoring of pathological changes in rodent livers during hyperoxia and hypercapnia.

Unlabelled: Liver diseases and regeneration are associated with hemodynamic changes denoting pathological alterations. Determining and monitoring physiological and pathological liver changes is essential for diagnostic and therapeutic objectives. Our aim was to determine the feasibility of functional magnetic resonance imaging (fMRI) during hypercapnia and hyperoxia for monitoring liver pathology.

Cell-autonomous and non-cell-autonomous functions of caspase-8.

Cells in vivo do not act in isolation. Therefore, when attempting to predict the results of pharmaceutical modulation of the function of a protein, we must also take into account the non-cell-autonomous consequences of such modulation. Studies of caspase-8 initially indicated that it serves as the proximal enzyme in cellular self-destruction dictated through the extrinsic cell-death pathway.

Liver response to hemorrhagic shock and subsequent resuscitation: MRI analysis.

The liver is a target for injury in low flow states. Markers of liver injury are either invasive or not rapidly responding. Magnetic resonance imaging (MRI) may offer a noninvasive alternative to evaluate liver injury due to reduced perfusion.

Functional MR imaging during hypercapnia and hyperoxia: noninvasive tool for monitoring changes in liver perfusion and hemodynamics in a rat model.

Purpose: To prospectively assess functional magnetic resonance (MR) imaging during hypercapnia and hyperoxia for monitoring changes in liver perfusion and hemodynamics in rats.

Materials And Methods: All experiments were performed with approval of an animal care and use committee. Functional T2*-weighted gradient-echo MR images of the rat liver were acquired during hyperoxia and graded hypercapnia (n=24).

Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice.

Dietary antioxidants and selenium compounds were shown to have a therapeutic effect against hepatocellular carcinoma in several mouse models. We tested the effects of tannic acid and selenomethionine on hepatocellular carcinoma development in Mdr2 knockout (Mdr2-KO) mice. Mdr2-KO and age-matched Mdr2 heterozygous control mice were fed with tannic acid or selenomethionine during the first 3 months of life.

Role of caspase-8 in hepatocyte response to infection and injury in mice.

Unlabelled: Caspase-8 has been implicated in signaling for apoptotic cell death and for certain nonapoptotic functions. However, knowledge of actual physiological or pathophysiological processes to which this enzyme contributes is lacking. Using a mouse model and employing the conditional knockout approach to delete the caspase-8 gene specifically in the liver, we found that caspase-8 deficiency in hepatocytes facilitates infection of the liver by Listeria monocytogenes, attenuates the hepatocyte proliferation wave during the first 48 hours after partial hepatectomy and, depending on the genetic background of the mice, prompts a chronic inflammatory response to the hepatectomy, as a result of which the proliferation of hepatocytes, although initially suppressed, might later be persistently enhanced, resulting in significant hepatomegaly.

Multiple adaptive mechanisms to chronic liver disease revealed at early stages of liver carcinogenesis in the Mdr2-knockout mice.

Molecular events preceding the development of hepatocellular carcinoma were studied in the Mdr2-knockout (Mdr2-KO) mice. These mice lack the liver-specific P-glycoprotein responsible for phosphatidylcholine transport across the canalicular membrane. Portal inflammation ensues at an early age followed by hepatocellular carcinoma development after the age of 1 year.

Redesigning the care of fragility fracture patients to improve osteoporosis management: a health care improvement project.

Objective: To develop new processes that assure more reliable, population-based care of fragility fracture patients.

Methods: A 4-year clinical improvement project was performed in a multispecialty, community practice health system using evidence-based guidelines and rapid cycle process improvement methods (plan-do-study-act cycles).

Results: Prior to this project, appropriate osteoporosis care was provided to only 5% of our 1999 hip fracture patients.