Cumulative Dose of Prostaglandin E1 Determines Gastrointestinal Adverse Effects in Term and Near-Term Neonates Awaiting Cardiac Surgery: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to assess the association between treatment characteristics of prostaglandin E1 including initiation time and duration, maximal and cumulative doses, and adverse effects. DESIGN: A retrospective cohort study in which medical records of neonates with duct-dependent lesions were studied for treatment parameters and adverse effects. Multivariable logistic regression model was applied for testing the effect PGE1 variables on outcomes. MAIN OUTCOME MEASURES: The primary outcomes of this study were association of adverse effects of PGE1 treatment with maximal dose, cumulative dose, and treatment duration. The secondary outcomes included safety of feeding in infants treated with PGE1. RESULTS: Eighty-two infants with duct-dependent lesions receiving PGE1 were included. Several infants who received early PGE1 treatment required ventilation support. Feeds were ceased more often as the cumulative dose and duration of PGE1 treatment increased. Gastrointestinal adverse effects were significantly associated with the cumulative dose of PGE1 and treatment duration. Apneas, hyperthermia, and tachycardia were associated with maximal dose. Our data did not demonstrate a difference in the incidence of NEC associated with characteristics of PGE1 treatment. CONCLUSION: Cumulative PGE1 dose is associated with gastrointestinal adverse effects in neonates. Lower doses should be considered in neonates expecting prolonged PGE1 treatment.

Changes in ventilation modes in the last decade and their impact on the prevalence of bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Less invasive forms of ventilation have evolved aiming to decrease bronchopulmonary dysplasia (BPD) morbidity. It is unclear whether changes in ventilation practices have been associated with improvements in respiratory outcomes. OBJECTIVE: To examine the changes in ventilation modes in preterm neonates between two periods during the last decade and their impact on BPD prevalence. METHODS: A retrospective chart review of very low birth weight infants and those born at less than 32 weeks gestation hospitalized during two periods: the years 2012-2013 and 2018-2019. The primary outcome was the prevalence of BPD. Study variables included the mode and duration of ventilation, duration of oxygen need, and perinatal clinical parameters. RESULTS: Four hundred eighty-one infants were enrolled. Between the two study periods, a significant increase was observed in invasive (33%-47%, p = 0.002), and noninvasive ventilation rates (44%-72%, p < 0.001). The average duration of noninvasive ventilation increased significantly (from 9.24 to 14.08 days, p = 0.016). The total duration of respiratory support remained unchanged. The overall prevalence of moderate and severe BPD at 36 weeks corrected age remained approximately 40% in preterm infants born at less than 28 weeks gestation. CONCLUSION: The increasing use of non-invasive ventilation was not accompanied by a reduction in the use of invasive ventilation, nor by a reduced prevalence of BPD. The high prevalence of BPD remains a significant problem in extreme prematurity. Other interventions, in addition to less aggressive ventilation, need to be explored.

Neonatal morbidities and postnatal growth failure in very low birth weight, very preterm infants.

AIM: To assess postnatal growth in infants with and without major neonatal morbidities. METHODS: This study is based on analysis of data collected by the Israel Neonatal Network on VLBW infants (≤1500 g) born in Israel from 2009 to 2018. Postnatal growth was assessed in two 5 years epochs: 2009-2013 (n = 4583) and 2014-2018 (n = 4558). Outcome was considered as severe, mild and no postnatal growth failure (PNGF). Morbidities included respiratory distress syndrome, bronchopulmonary dysplasia, necrotising enterocolitis, patent ductus arteriosus and grades 3-4 intraventricular haemorrhage. Multinomial logistic regression analyses with the generalised estimating equation approach were applied. RESULTS: The study population composed 9141 infants. Of them, 2089 had at least one major morbidity and 7052 infants had none. In infants with no morbidities, 2.1% had severe PNGF, 23.7% mild PNGF and 74.2% had no PNGF, as compared to 13.6%, 43.9% and 42.5%, respectively, in infants with any major neonatal morbidity (p < 0.0001). CONCLUSION: Despite enormous advances in neonatal care, postnatal growth remains a challenge in VLBW infants, particularly in infants with major neonatal morbidities. Along with efforts to decrease morbidity, a more personalised plan and follow-up may be required in infants with major morbidities, given their high risk for diminished growth and potentially, adverse neurodevelopmental outcomes.

De novo variant in AMOTL1 in infant with cleft lip and palate, imperforate anus and dysmorphic features.

AMOTL1 belongs to the Motin family of proteins that are involved in organogenesis and tumorigenesis through regulation of cellular migration, tube formation, and angiogenesis. While involvement of all AMOTs in development or suppression of cancers is relatively well described, little is known about the congenital phenotype of pathogenic variants in these genes in humans. Recently, a heterozygous variant in AMOTL1 was published in association with orofacial clefts and cardiac abnormalities in an affected father and his daughter. However, studies in mice did not recapitulate the human phenotype and the case was summarized as inconclusive. We present a female infant with cleft lip and palate, imperforate anus and dysmorphic features, in whom trio exome sequencing revealed a de novo variant in AMOTL1 affecting a highly conserved amino acid (c.479C>T; p.[Pro160Leu]). Bioinformatic predictions and in silico modeling supported pathogenicity. This case reinforces the conjecture regarding the disruptive effect of pathogenic variants in AMOTL1 on organ formation in humans. Studies of additional families will reveal the full phenotypic spectrum associated with this multiple malformation syndrome.

Homozygous variants in MAPRE2 and CDON in individual with skin folds, growth delay, retinal coloboma, and pyloric stenosis.

Cases with multiple molecular diagnoses are challenging to diagnose clinically, yet may be resolved by unbiased exome sequencing analysis. We report an infant with developmental delay, severe growth delay, dysmorphic features, and multiple congenital anomalies including retinal coloboma, congenital pyloric stenosis, and circumferential skin creases. Exome sequencing identified a homozygous missense variant in MAPRE2 and a homozygous stopgain (nonsense) variant in CDON. Variants in MAPRE2, encoding a regulator of microtubule dynamics, lead to congenital symmetric circumferential skin creases type 2, with associated dysmorphism, small growth parameters, and congenital cardiac and genital anomalies. Monoallelic variants in CDON, encoding a coreceptor for sonic hedgehog, have been associated with autosomal dominant pituitary stalk interruption syndrome and holoprosencephaly. Cdon-/- mice have multiple eye defects including coloboma, consistent with the observed human phenotype. Thus, the complex phenotypic presentation of the infant may potentially be attributed to a dual molecular diagnosis. Furthermore, we present CDON as a candidate gene for coloboma formation in addition to the known holoprosencephaly phenotype, and propose to expand the allelic spectrum of CDON to variants associated with autosomal recessive inheritance in addition to dominant inheritance.

Saliva Real-Time Polymerase Chain Reaction for Targeted Screening of Congenital Cytomegalovirus Infection.

BACKGROUND: Saliva real-time polymerase chain reaction (PCR) was shown to be sensitive and specific for the detection of congenital cytomegalovirus (cCMV) in universal screening studies. In the current study, we assessed the performance of saliva real-time PCR in newborns undergoing targeted cCMV screening. METHODS: Saliva real-time PCR results were prospectively correlated with reference-standard urine detection in newborns undergoing targeted cCMV screening over a 3-year period, in successive validation (concurrent testing of all saliva and urine specimens) and routine-screening (confirmatory urine testing of positive saliva results) implementation phases. RESULTS: The sensitivity, specificity, and positive and negative predictive values of saliva real-time PCR were 98.3% (95% confidence interval, 90.8%-99.9%), 91.5% (89.3%-93.3%), 45.6% (36.7%-54.7%), and 99.9% (99.2%-99.9%), respectively, in 856 concurrently tested newborns. True-positive saliva real-time PCR detection (defined in relation to urine detection) was associated with earlier saliva sampling (P = .002) and a higher saliva viral load (P < .001). We further identified a saliva viral load cutoff value that reliably distinguished between true-positive and false-positive saliva results. CONCLUSIONS: In newborns undergoing targeted screening for cCMV, saliva real-time PCR is highly sensitive yet has a low positive predictive value, necessitating confirmatory testing. Early sampling and application of a validated viral load cutoff could improve the assay performance and support its large-scale implementation in this growing clinical setting.

Retrospective cohort study to investigate the impact of timing for term cesarean delivery on maternal and neonatal outcomes.

BACKGROUND: Early-term cesarean delivery (CD) increases neonatal respiratory morbidity; however, planned late-term cesarean delivery (CD) may generate urgent CD related to spontaneous onset of labor. AIMS: We investigated maternal and neonatal morbidity for planned early (37/38 week) versus late-term (39/40 weeks) CD. Our primary study aim was to investigate severe maternal morbidity and general anesthesia rates according to early versus late-term CD. Our secondary study aims were to investigate the rate of urgent surgery and other measures of maternal morbidity, and neonatal morbidity, according to early versus late-term CD and according to urgent versus elective planned CD. METHODS: In our retrospective, ethically approved study of planned CD we compared maternal morbidity and neonatal respiratory morbidity, for early versus late-term CD. RESULTS: Among 370 early versus 300 late-term CD, women who delivered at late-term CD had significantly higher rates of urgent surgery 101 (33.7%) versus 85 (23.0%) at early-term, p = .002; spontaneous onset of labor 85 (28.3%) versus 67 (18.1%), p = .0002 and out-of-hours surgery 101 (33.7%) versus 64 (17.3%), p < .0001. The frequency of neonatal respiratory morbidity composite was 10 (2.7%) for early versus 1 (0.3%) for late-term CD, p = .03. CONCLUSIONS: Late-term CD was not associated with increased maternal morbidity or use of general anesthesia in our tertiary institution. Prior reports of increased neonatal respiratory morbidity at early term CD were confirmed. Of concern, late-term CD was associated with urgent and out-of-hours CD.

[ADVANCES IN FETAL THERAPY IN COMPLICATED MONOCHORIONIC PREGNANCIES AND IN SEVERE CONGENITAL DIAPHRAGMATIC HERNIA: FIVE YEARS EXPERIENCE].

INTRODUCTION: : Minimally invasive fetal therapeutic procedures reduce the morbidity and mortality in monochorionic (MC) twins and in fetuses with congenital diaphragmatic hernia (CDH). MC pregnancies share their blood systems due to communicating vessels over their single placenta and may develop specific complications: Twin-to-Twin transfusion syndrome (TTTS), Selective intrauterine growth restriction (sIUGR), Twin Anemia-Polycythemia Sequence (TAPS), Twin Reverse Arterial Perfusion Syndrome (TRAP) or anomalies in one. Half of complicated MC require intrauterine interventions. Severe CDH is linked to a high rate of neonatal death due to pulmonary hypoplasia. Fetoscopic tracheal occlusion (FETO) with a balloon improves postnatal outcome. AIMS: A fetal therapy center was established in the Hadassah Medical Centers, Jerusalem in 2011 for intrauterine interventions. We report our 5 years' experience. METHODS: This prospective cohort follows the outcome of MC pregnancies and cases of severe CDH which underwent therapeutic fetal procedures in Hadassah between the years 2011-16. RESULTS: Out of 114 procedures, 95 were in MC: 84 monochorionic diamniotic twins, 7 monochorionic monoamniotic twins, 2 dichorionic triamniotic triplets and 2 monochorionic triplets. We treated 65 TTTS cases with fetoscopy and laser ablation of communicating vessels. The survival rate of both twins was 58.5% and at least one survived in 81.5% of the cases. In 2nd/3rd trimesters selective termination of 15 cases the survival rate of the remaining twin was 87%. In 11 cases of TRAP sequence treated with laser ablation of the feeding vessel the survival of the remaining twin was 91%. In 19 fetoscopies in severe CDH, 12 were for balloon insertion and 7 for removal. Endotracheal balloon was successfully placed in 11 of 12 cases (10 left-sided, 1 right-sided CDH). Balloon removal was prenatally performed by elective fetoscopy (n=7) or by intrapartum urgent puncture. There were no intrauterine fetal deaths. In isolated left-sided CDH the survival was 57%, whereas none survived in non-isolated left-sided CDH and right sided CDH. CONCLUSIONS: In-utero procedures are safe for the mother and increase newborn survival in MC pregnancies, thus specialized clinics are life-saving. FETO is a therapeutic option for severe CDH. Our results meet similar achievements reported by other leading world centers.

Transaldolase Deficiency: A New Case Expands the Phenotypic Spectrum.

Transaldolase (TALDO) deficiency has various clinical manifestations including liver dysfunction, hepatosplenomegaly, anemia, thrombocytopenia, and dysmorphic features. We report a case presenting prenatally with hyperechogenic bowel and intrauterine growth restriction. The infant was born small for gestational age, with cutis laxa and hypertrichosis. Postnatally, meconium plug was identified, complicated with intestinal obstruction necessitating laparotomy, partial resection of the intestine, and ileostomy. Liver biopsy revealed cholangiolar proliferation and portal fibrosis. He also suffered from persistent congenital thrombocytopenia requiring platelet transfusions and severe hypothyroidism with normal anatomical and structural gland responding only to the combination of T3 and T4 treatment. Neurologically, severe hypotonia and anisocoria were noted at the age of 2 months. Brain MRI was normal. Shortly after the abdominal surgery, a rapid liver failure ensued, which eventually led to his death. Specific metabolic tests ruled out glycosylation disorders, yet urine analysis using 1H NMR showed accumulation of sedoheptulose which was previously described in patients with transaldolase deficiency. Sequencing of the gene-encoding transaldolase (TALDO1) revealed a homozygous stop mutation c.669C>G; p.Tyr223*. In conclusion, we present an infant with a novel homozygous mutation in TALDO1, causing TALDO deficiency, and extend the clinical characteristics of this rare syndrome.

Parents' knowledge and perceptions regarding vitamin K prophylaxis in newborns.

BACKGROUND: There is an increasing trend of parents refusing vitamin K (VK) prophylaxis in newborns. We examined the knowledge, perceptions, cultural and religious barriers of expecting parents regarding VK prophylaxis. OBSERVATIONS: Questionnaires were completed by 217 participants: 151 female participants and 85% were expecting their first child. Two thirds had academic degrees, yet were ignorant regarding recommendation to provide VK (22.5%), source (15.5%), action (34%), and provision options (29%). Moreover, first-time parents had not yet decided to provide VK after birth (P<0.05). CONCLUSIONS: There is a need to provide expecting parents with information regarding safety, utility, and benefits of VK prophylaxis.

The use of blood counts and blood cultures to screen neonates born to partially treated group B Streptococcus-carrier mothers for early-onset sepsis: is it justified?

BACKGROUND: No clear recommendations exist regarding the approach to evaluate neonates born to partially treated group B Streptococcus (GBS)-carrier mothers for early-onset GBS (EO-GBS) sepsis. OBJECTIVE: To determine the yield and drawbacks of screening, all neonates born to GBS-carrier mothers who received only one dose of IV antibiotic, less than 4 hours, before delivery (partially treated). METHODS: A retrospective analysis was performed of all complete blood counts (CBCs) and blood cultures obtained from infants born during the period 2005 to 2009 to GBS-positive screened mothers treated with only one dose of antibiotic prior to delivery. A review was conducted of all neonatal EO-GBS sepsis cases during the study period. RESULTS: : Of 5845 GBS-carrier mothers, 1648 (28%) received only one dose of antibiotic less than 4 hours before delivery. We traced the CBCs and blood cultures, which were taken from 1413/1648 (86%) infants after birth. In 234 (18%) of these 1413 neonates, a second CBC sample was taken due to abnormal result of the CBC (leukocytosis, leukopenia, or thrombocytopenia) or secondary to technical failure in obtaining the blood. None of the blood cultures taken in that screening protocol was GBS positive, but in 10 cases contamination with coagulase-negative Staphylococcus was reported. During the study period, EO-GBS sepsis was diagnosed in 11 neonates; all had clinical symptoms upon presentation. CONCLUSIONS: The use of CBC and blood culture to screen neonates born to GBS-carrier mothers who received only one dose of IV antibiotic before delivery led to a negligible clinical yield and a high rate of technical failure. Although these findings are in line with the recent change in the Centers for Disease Control guidelines, they put in question the cost of this practice in terms of neonatal pain and parental anxiety.

The red reflex examination in neonates: an efficient tool for early diagnosis of congenital ocular diseases.

BACKGROUND: The American Academy of Pediatrics recently published recommendations for the red reflex assessment in the newborn period to detect and treat ocular disorders as early as possible, and to prevent lifelong visual impairment and even save lives. The test is technically simple to perform, non-invasive, requires minimal equipment and can detect a variety of ocular pathologies including cataracts and retinal abnormalities. No specific national guidelines exist on this issue. OBJECTIVES: To document the implementation of red reflex examination in routine neonatal care and present the findings. METHODS: Our clinical experience following inclusion of the red reflex test into the newborn physical examination in a single center was reviewed. In addition, an electronic mail questionnaire was sent to all neonatology departments in Israel regarding performance of the red reflex test. RESULTS: During 2007-2008, five infants were identified with congenital cataracts at days 2-6 of life prior to discharge from hospital. Surgery was performed in one infant at age 2 months and all infants underwent a thorough follow-up. The incidence of congenital cataract in our center was 1:2300. Less than half the neonatology departments have endorsed the AAP recommendation and perform the red reflex test routinely. CONCLUSIONS: Abnormal red reflex test after delivery enables a rapid ophthalmologic diagnosis, intervention and close followup. We recommend that red reflex screening be performed as part of the newborn physical examination; if abnormal, an urgent ophthalmologic referral should be made.

Growth enhancement by embryonic fibroblasts upon cotransplantation of noncommitted pig embryonic tissues with fully committed organs.

BACKGROUND: We recently defined the optimal gestational time windows for the transplantation of several embryonic tissues. We showed that the liver and kidney obtained from E28 pig embryos can grow and differentiate normally after transplantation, whereas 1 week earlier in gestation, these tissues develop into teratoma-like structures or fibrotic mass. In this study, we investigated whether cotransplantation of E28 with E21 tissue could control its tumorogenic potential, or alternatively whether the stem cells derived from the earlier tissue contribute to the growth of the more committed one. METHODS: Pig embryonic precursors from E21 and E28 gestational age were transplanted alone or together, into nonobese diabetic/severe combined immunodeficiency mice, and their growth and differentiation was evaluated by immunohistology. In situ analysis, based on sex disparity between the E21 and E28 tissues, was used to identify the tissue source. In some experiments, mouse embryonic fibroblasts (MEF) were cotransplanted with E28 liver, and their effect was evaluated. RESULTS: E28 tissues could not abrogate the propensity of the cells within the undifferentiated tissue to form teratoma-like structures. However, E21 kidney or liver tissue markedly enhanced the growth and function of E28 kidney, liver, and heart grafts. Moreover, similar growth enhancement was observed on coimplantation of E28 liver tissue with MEF or on infusion of MEF culture medium, indicating that this enhancement is likely mediated through soluble factors secreted by the fibroblasts. CONCLUSION: Our results suggest a novel approach for the enhancement of growth and differentiation of transplanted embryonic tissues by the use of soluble factors secreted by embryonic fibroblasts.

Third trimester fetal intracranial hemorrhage owing to vitamin K deficiency associated with hyperemesis gravidarum.

In rare cases, severe fetal vitamin K deficiency bleeding may occur in utero as a result of insufficient vitamin K placental transfer. We present a case of a 32-week-preterm infant born with severe intracranial hemorrhage to a pregnant woman who suffered from hyperemesis gravidarum. Neonatal hematologic status was compatible with vitamin K deficiency whereas the maternal coagulation function was normal. This case emphasizes the potential risk of fetal bleeding owing to vitamin K deficiency in pregnancies complicated with hyperemesis gravidarum. These women should be closely monitored and vitamin K prophylaxis might be considered.

Enhancement of pig embryonic implants in factor VIII KO mice: a novel role for the coagulation cascade in organ size control.

Very little is known about the mechanisms that contribute to organ size differences between species. In the present study, we used a mouse model of embryonic pig tissue implantation to define the role of host Factor VIII in controlling the final size attained by the implant. We show here that pig embryonic spleen, pancreas, and liver all grow to an increased size in mice that are deficient in the Factor VIII clotting cascade. Similar results were obtained using the transplantation model after treatment with the low molecular weight heparin derivative Clexane which markedly enhanced transplant size. Likewise, enhanced size was found upon treatment with the direct thrombin inhibitor Dabigatran, suggesting that organ size regulation might be mediated by thrombin, downstream of Factor VIII. Considering that thrombin was shown to mediate various functions unrelated to blood clotting, either directly by cleavage of protease-activated receptors (PARs) or indirectly by cleaving osteopontin (OPN) on stroma cells, the role of PAR1 and PAR4 antagonists as well as treatment with cleaved form of OPN (tcOPN) were tested. While the former was not found to have an impact on overgrowth of embryonic pig spleen implants, marked reduction of size was noted upon treatment with the (tcOPN). Collectively, our surprising set of observations suggests that factors of the coagulation cascade have a novel role in organ size control.

Embryonic porcine liver as a source for transplantation: advantage of intact liver implants over isolated hepatoblasts in overcoming homeostatic inhibition by the quiescent host liver.

Cell therapy as an alternative to orthotopic liver transplantation represents a major challenge, since negligible proliferation of isolated hepatocytes occurs after transplantation because of the stringent homeostatic control displayed by the host liver. Thus, different modalities of liver injury as part of the pretransplant conditioning are a prerequisite for this approach. The major objective of the present study was to test whether xenotransplantation of pig fetal liver fragments, in which potential cell-cell and cell-stroma interactions are spared, might afford more robust growth and proliferation compared with isolated pig fetal hepatoblasts. After transplantation into SCID mice, fetal liver tissue fragments exhibited marked growth and proliferation, in the setting of a quiescent host liver, compared with isolated fetal hepatoblasts harvested at the same gestational age (embryonic day 28). The proliferative advantage of fetal pig liver fragments was clearly demonstrated by immunohistochemical and morphometric assays and was observed not only after implantation into the liver but also into extrahepatic sites, such as the spleen and the subrenal capsule. The presence of all types of nonparenchymal liver cells that is crucial for normal liver development and regeneration was demonstrated in the implants. Preservation of the three-dimensional structure in pig fetal liver fragments enables autonomous proliferation of transplanted hepatic cells in the setting of a quiescent host liver, without any requirement for liver injury in the pretransplant conditioning. The marked proliferation and functional maturation exhibited by the pig fetal liver fragments suggests that it could afford a preferable source for transplantation.

Isolation and characterization of nontubular sca-1+lin- multipotent stem/progenitor cells from adult mouse kidney.

Tissue engineering and cell therapy approaches aim to take advantage of the repopulating ability and plasticity of multipotent stem cells to regenerate lost or diseased tissue. Recently, stage-specific embryonic kidney progenitor tissue was used to regenerate nephrons. Through fluorescence-activated cell sorting, microarray analysis, in vitro differentiation assays, mixed lymphocyte reaction, and a model of ischemic kidney injury, this study sought to identify and characterize multipotent organ stem/progenitor cells in the adult kidney. Herein is reported the existence of nontubular cells that express stem cell antigen-1 (Sca-1). This population of small cells includes a CD45-negative fraction that lacks hematopoietic stem cell and lineage markers and resides in the renal interstitial space. In addition, these cells are enriched for beta1-integrin, are cytokeratin negative, and show minimal expression of surface markers that typically are found on bone marrow-derived mesenchymal stem cells. Global gene profiling reveals enrichment for many genes downstream of developmental signaling molecules and self-renewal pathways, such as TGF-beta/bone morphogenic protein, Wnt, or fibroblast growth factor, as well as for those that are involved in specification of mesodermal lineages (myocyte enhancer factor 2A, YY1-associated factor 2, and filamin-beta). In vitro, they are plastic adherent and slowly proliferating and result in inhibition of alloreactive CD8(+) T cells, indicative of an immune-privileged behavior. Furthermore, clonal-derived lines can be differentiated into myogenic, osteogenic, adipogenic, and neural lineages. Finally, when injected directly into the renal parenchyma, shortly after ischemic/reperfusion injury, renal Sca-1(+)Lin(-) cells, derived from ROSA26 reporter mice, adopt a tubular phenotype and potentially could contribute to kidney repair. These data define a unique phenotype for adult kidney-derived cells, which have potential as stem cells and may contribute to the regeneration of injured kidneys.

Embryonic pig pancreatic tissue transplantation for the treatment of diabetes.

BACKGROUND: Transplantation of embryonic pig pancreatic tissue as a source of insulin has been suggested for the cure of diabetes. However, previous limited clinical trials failed in their attempts to treat diabetic patients by transplantation of advanced gestational age porcine embryonic pancreas. In the present study we examined growth potential, functionality, and immunogenicity of pig embryonic pancreatic tissue harvested at different gestational ages. METHODS AND FINDINGS: Implantation of embryonic pig pancreatic tissues of different gestational ages in SCID mice reveals that embryonic day 42 (E42) pig pancreas can enable a massive growth of pig islets for prolonged periods and restore normoglycemia in diabetic mice. Furthermore, both direct and indirect T cell rejection responses to the xenogeneic tissue demonstrated that E42 tissue, in comparison to E56 or later embryonic tissues, exhibits markedly reduced immunogenicity. Finally, fully immunocompetent diabetic mice grafted with the E42 pig pancreatic tissue and treated with an immunosuppression protocol comprising CTLA4-Ig and anti-CD40 ligand (anti-CD40L) attained normal blood glucose levels, eliminating the need for insulin. CONCLUSIONS: These results emphasize the importance of selecting embryonic tissue of the correct gestational age for optimal growth and function and for reduced immunogenicity, and provide a proof of principle for the therapeutic potential of E42 embryonic pig pancreatic tissue transplantation in diabetes.

Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells.

Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of adult human liver cells into functional insulin-producing cells. PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner. When transplanted under the renal capsule of diabetic, immunodeficient mice, the cells ameliorated hyperglycemia for prolonged periods of time. Inducing developmental redirection of adult liver offers the potential of a cell-replacement therapy for diabetics by allowing the patient to be the donor of his own insulin-producing tissue.