Amir Weissman

Human Embryonic and Induced Pluripotent Stem Cell–Derived Cardiomyocytes Exhibit Beat Rate Variability and Power-Law Behavior

Background— The sinoatrial node is the main impulse-generating tissue in the heart. Atrioventricular conduction block and arrhythmias caused by sinoatrial node dysfunction are clinically important and generally treated with electronic pacemakers. Although an excellent solution, electronic pacemakers incorporate limitations that have stimulated research on biological pacing. To assess the suitability of potential biological pacemakers, we tested the hypothesis that the spontaneous electric activity of human embryonic stem cell–derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) exhibit beat rate variability and power-law behavior comparable to those of human sinoatrial node. Methods and Results— We recorded extracellular electrograms from hESC-CMs and iPSC-CMs under stable conditions for up to 15 days. The beat rate time series of the spontaneous activity were examined in terms of their power spectral density and additional methods derived from nonlinear dynamics. The major findings were that the mean beat rate of hESC-CMs and iPSC-CMs was stable throughout the 15-day follow-up period and was similar in both cell types, that hESC-CMs and iPSC-CMs exhibited intrinsic beat rate variability and fractal behavior, and that isoproterenol increased and carbamylcholine decreased the beating rate in both hESC-CMs and iPSC-CMs. Conclusions— This is the first study demonstrating that hESC-CMs and iPSC-CMs exhibit beat rate variability and power-law behavior as in humans, thus supporting the potential capability of these cell sources to serve as biological pacemakers. Our ability to generate sinoatrial-compatible spontaneous cardiomyocytes from the patients own hair (via keratinocyte-derived iPSCs), thus eliminating the critical need for immunosuppression, renders these myocytes an attractive cell source as biological pacemakers.

Sonographic measurements of the umbilical cord and vessels during normal pregnancies

Sonographic measurements of the umbilical cord and vessels were performed in 368 uncomplicated pregnancies, and nomograms of their growth were constructed. All measurements were obtained in appropriate for gestational age fetuses in pregnancies with accurate dating. From the above measurements, an estimate of Whartons jelly quantity (expressed as square millimeters) was calculated. The nomograms presented add another biometric measurement of normally growing fetuses and may serve to differentiate between them and those who are found to have umbilical cord abnormalities.

Uterine rupture following conservative surgery for interstitial pregnancy

A case of uterine rupture following conservative surgery for interstitial pregnancy is presented. Even though the uterine cavity was not opened during removal of the ectopic pregnancy, attenuation of the muscle lead to subsequent rupture of the uterus in the second trimester. The option for medical termination of ectopic pregnancies located in the cornual portion of tubes is discussed.

Hemivertebra: Prenatal Diagnosis, Incidence and Characteristics

Objective: Hemivertebra is a rare congenital spinal anomaly where only one side of the vertebral body develops, resulting in deformation of the spine, such as scoliosis, lordosis, or kyphosis. We aimed to determine the incidence and clinical characteristics of hemivertebra. Patients and Methods: We present three fetuses with a prenatal ultrasonographic diagnosis of hemivertebra at 15–22 weeks’ gestation, and we determine the incidence and clinical characteristics of hemivertebra among 78,500 live-born infants at a tertiary medical center in Israel. Results: There were 26 cases of hemivertebra (0.33/1,000 live-born infants): male/female ratio 1/1, Jewish/Arab ratio 10/16, and ratio of single/multiple type of hemivertebrae 17/9. Twenty-three out of 26 infants (88.5%) with hemivertebra had additional congenital anomalies (cranial, cardiac, renal, intestinal, and skeletal). Conclusions: Hemivertebra is not an infrequent finding in fetuses and live-born infants. Comprehensive ultrasonographic screening of the fetus allows early prenatal diagnosis of hemivertebra, and provides parents with helpful information for their decision regarding the fate of pregnancy.

Heel-Lancing in Newborns: Behavioral and Spectral Analysis Assessment of Pain Control Methods

OBJECTIVE: Pain experience can alter clinical outcome, brain development, and subsequent behavior in newborns, primarily in preterm infants. The aims of this study were (1) to evaluate several simple, commonly used methods for pain control in newborns and (2) to evaluate the concordance between behavioral and autonomic cardiac reactivity to pain in term neonates during heel-lancing. METHODS: A prospective study was conducted of 180 term newborn infants who were undergoing heel-lancing for routine neonatal screening of phenylketonuria and hypothyroidism. Newborns were assigned to 6 groups: (1) control (no pain relief intervention); (2) nonnutritive sucking; (3) holding by mother; (4) oral glucose solution; (5) oral formula feeding; or (6) breastfeeding. Outcome measures included the Neonatal Facial Coding System score; cry duration; and autonomic variables obtained from spectral analysis of heart rate variability before, during, and after heel-lancing. RESULTS: Infants with no pain control showed the highest pain manifestation compared with newborns to whom pain control was provided. Infants who breastfed or received an oral formula showed the lowest increase in heart rate (21 and 23 beats per minute, respectively, vs 36; P < .01), lowest neonatal facial score (2.3 and 2.9, respectively, vs 7.1; P < .001), lowest cry duration (5 and 13 seconds, respectively, vs 49; P < .001), and lowest decrease in parasympathetic tone (−2 and −2.4, respectively, vs 1.2; P < .02) compared with the other groups. CONCLUSIONS: Any method of pain control is better than none. Feeding and breastfeeding during heel-lancing were found to be the most effective methods of pain relief.

SCREENING FOR NEURAL TUBE DEFECTS

Neural tube defects are separated into two main categories: (1) abnormalities of the skull and brain (anencephaly, acrania, and encephalocele) and (2) malformations of the spine (meningomyelocele or spina bifida). The cause of neural tube defects is not always clear, and include chromosomal abnormalities, single gene mutations, maternal disease, or maternal exposure to teratogens. Mostly the disorder emerges as a multifactorial trait. Routine screening for neural tube defects was introduced in the United Kingdom in the mid-1970s and the United States in the mid-1980s. The use of screening has resulted in a marked decline in the frequency of neural tube defects diagnosed at birth.

The influence of increased seismic activity on pregnancy outcome

The influence of increased seismic activity on pregnancy outcome was evaluated. A significant increase in delivery rate was noted during the 48 hours following an earthquake on all instances. In two out of five events, a significant increase in premature delivery rate was noted (p less than 0.05). Possible signs of fetal distress in utero were documented following these events.

Single-dose cefazolin prophylaxis for cesarean section

In a prospective, randomized trial, the efficacy of a single-dose, first-generation, long-acting cephalosporin was compared with a three-dose regimen in a group of 100 women undergoing cesarean section who were at high risk for postoperative febrile morbidity. Fifty women received a single 1 gm intravenous dose of cefazolin and 50 received 1 gm of the drug followed by two additional doses, 8 hours apart, to complete a three-dose regimen. Another 50 women, considered to be at low risk for postoperative febrile morbidity, were not given antibiotic prophylaxis. Outcomes of febrile morbidity (18% vs 12%) and particularly morbidity caused by endometritis (6% vs 8%, respectively) were similar for single-dose and three-dose groups. In the untreated low-risk group there were no cases of endometritis and the febrile morbidity was comparable to that of the prophylactically treated groups (14% vs 15%). Single-dose cefazolin prophylaxis appears to be comparable to multidose prophylaxis in reducing febrile morbidity after cesarean section.

Sonographic measurement of amniotic fluid volume in the first trimester of pregnancy

The sonographic estimate of amniotic fluid volume from 7 to 13 weeks of gestation in 95 pregnancies was calculated. Amniotic fluid volume increased from 1.5 ml at 7 weeks to 25 ml at 10 weeks and 100 ml at 13 weeks. The nomograms constructed may be used in the objective evaluation of the fetal condition in the first trimester.

From beat rate variability in induced pluripotent stem cell-derived pacemaker cells to heart rate variability in human subjects.

BACKGROUND We previously reported that induced pluripotent stem cell-derived cardiomyocytes manifest beat rate variability (BRV) resembling heart rate variability (HRV) in the human sinoatrial node. We now hypothesized the BRV-HRV continuum originates in pacemaker cells. OBJECTIVE To investigate whether cellular BRV is a source of HRV dynamics, we hypothesized 3 levels of interaction among different cardiomyocyte entities: (1) single pacemaker cells, (2) networks of electrically coupled pacemaker cells, and (3) the in situ sinoatrial node. METHODS We measured BRV/HRV properties in single pacemaker cells, induced pluripotent stem cell-derived contracting embryoid bodies (EBs), and electrocardiograms from the same individual. RESULTS Pronounced BRV/HRV was present at all 3 levels. The coefficient of variance of interbeat intervals and Poincaré plot indices SD1 and SD2 for single cells were 20 times greater than those for EBs (P < .05) and the in situ heart (the latter two were similar; P > .05). We also compared BRV magnitude among single cells, small EBs (~5-10 cells), and larger EBs (>10 cells): BRV indices progressively increased with the decrease in the cell number (P < .05). Disrupting intracellular Ca(2+) handling markedly augmented BRV magnitude, revealing a unique bimodal firing pattern, suggesting that intracellular mechanisms contribute to BRV/HRV and the fractal behavior of heart rhythm. CONCLUSION The decreased BRV magnitude in transitioning from the single cell to the EB suggests that the HRV of in situ hearts originates from the summation and integration of multiple cell-based oscillators. Hence, complex interactions among multiple pacemaker cells and intracellular Ca(2+) handling determine HRV in humans and cardiomyocyte networks.