Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing.

Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs. Although several families with MANDP have been reported, homozygous mutations in the matrix metalloproteinase type 9 (MMP9) gene have been described in only one consanguineous family, and thus the pre and postnatal phenotypic spectrum is still obscure. A clinically similar but more severe type is caused by autosomal-dominant inheritance and is caused by mutations in matrix metalloproteinase type 13 gene (MMP13). Here, we report the prenatal and early postnatal course of two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses suggesting a diagnosis of MANDP. We propose that MANDP should be considered in pregnancies with early prenatal shortening of the long bones without associated finding of lethal skeletal dysplasias. In addition, the finding of homozygous mutation in non-consanguineous parents of Jewish-Caucasus ancestry may suggest unawareness of such relation or the occurrence of a founder mutation in this gene.

Chromosomal microarray analysis in fetuses with aberrant right subclavian artery.

OBJECTIVE: To evaluate the association between aberrant right subclavian artery (ARSA), with or without additional risk factors for aneuploidy or ultrasound abnormality, and results of chromosomal microarray analysis (CMA). METHODS: This was a multicenter study of fetuses diagnosed with ARSA that underwent genetic analysis by CMA, all samples being analyzed in the same laboratory. Clinical investigation included nuchal translucency measurement, first- and second-trimester maternal serum screening, early and late second-trimester fetal anatomy scans and fetal echocardiography. Comparative genomic hybridization microarray analysis or single-nucleotide polymorphism array technology was used for CMA of DNA samples obtained from amniotic fluid. RESULTS: CMA results were available for 63 fetuses with ARSA. In 36 fetuses, ARSA was an isolated finding, and no pathogenic variant was found. Additional ultrasound findings and/or risk factors for aneuploidy were present in 27 fetuses, five of which had pathogenic CMA results. Of these five, trisomy 21 was detected in a fetus with echogenic intracardiac focus (EIF), 22q11 deletion was detected in a fetus with EIF and an increased risk of trisomy 21 of 1:230 from maternal serum screening, 22q11 duplication was detected in a fetus with hypoplastic right kidney and choroid plexus cyst and 22q11 deletion was detected in a fetus with right aortic arch and clubfoot. The fifth fetus had increased nuchal translucency thickness (4 mm) and a ventricular septal defect, and CMA identified both 22q11 deletion and 1q21 duplication. CONCLUSIONS: In fetuses with isolated ARSA, an invasive procedure for CMA is not indicated. However, CMA is recommended when additional ultrasound abnormalities or risk factors for aneuploidy are observed. The chromosomal findings in four of the five cases with an abnormal CMA result in our study would not have been detected by standard fetal chromosomal testing. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Cut-off value of nuchal translucency as indication for chromosomal microarray analysis.

OBJECTIVES: An association between isolated, increased nuchal translucency thickness (NT) and pathogenic findings on chromosomal microarray analysis (CMA) has been reported. A recent meta-analysis reported that most studies use a NT cut-off value of 3.5 mm. However, considering NT distribution and the commonly accepted 5% false-positive rate in maternal serum screening, NT cut-off levels should be reconsidered. The aim of this study was to assess different NT cut-off levels as indication for CMA and to determine whether CMA should be recommended for mildly increased NT of 3.0-3.4 mm. METHODS: This was a retrospective, multicenter study of singleton pregnancies with CMA results and either normal NT and no other finding or with increased NT as the only medical indication for CMA at the time of an invasive procedure (increased NT was considered an isolated finding in cases of advanced maternal age). Women with normal fetal NT who underwent CMA did so at their own request. A single laboratory performed all genetic analyses. Comparative genomic hybridization microarray analysis or single nucleotide polymorphism array technology was used for CMA. If combined first-trimester screening (NT and biochemistry) indicated increased risk for common aneuploidies, the case was excluded. NT was used to divide cases into three groups (≤ 2.9 mm, 3.0-3.4 mm and ≥ 3.5 mm) and their CMA results were compared. RESULTS: CMA results were recorded in 1588 pregnancies, among which 770 fetuses had either normal NT with no other finding or isolated increased NT. Of these, 462 had NT ≤ 2.9 mm, 170 had NT of 3.0-3.4 mm and 138 had NT ≥ 3.5 mm. Pathogenic copy number variants were found in 1.7%, 6.5% and 13.8% of cases, respectively. CONCLUSION: Our results suggest that CMA should be recommended when fetuses have isolated, mildly increased NT (3.0-3.4 mm). Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Telomeres in trisomy 21 amniocytes.

Individuals with trisomy 21 have an increased risk of developing leukemia and premature dementia. They also have a higher rate of telomere loss. The aim of the study was to compare telomere length and the hTERC gene copy number, which encodes the telomerase RNA subunit, in amniocytes of trisomy 21 conceptions and normal pregnancies. A quantitative fluorescence-in-situ protocol (Q-FISH) was used to compare telomere length in amniocytes cultured from 11 trisomy 21 conceptions and from 14 normal pregnancies. Quantification was conducted using novel computer software. Fluorescence in situ hybridization (FISH) was used to assess the percentage of cells with additional copies of hTERC. We found that the immunofluorescence intensity, which represents telomere length, was significantly lower in amniocytes from trisomy 21 conceptions compared to the control group. The trisomy 21 group had a higher number of cells with additional copies of hTERC. This observation could be one of the cytogenetic parameters that represent a state of genetic instability and might play a role in the pathomechanism of typical features of Down syndrome, such as dementia and malignancy.

Dependence of maternal serum [AFP]/[hCG] median ratios on age of gestation: comparison of trisomy 21 to euploid pregnancies.

BACKGROUND: Current risk calculations for trisomy 21, which are based on multiples of median (MoM), do not take into account possible differences between euploid and trisomy 21 pregnancies that may develop with gestational age. In order to optimize the predictive value of screening tests, we calculated the ratio between maternal serum concentration of alpha-fetoprotein (AFP) and that of human chorionic gonadotropin (hCG) in euploid and in trisomy 21 pregnancies. METHODS: The medians of the concentration ratios, [AFP]/[hCG] at 16-21 weeks of gestation, were plotted as a function of gestational age for 307 cases of trisomy 21 and were compared with the medians of 30 549 normal karyotype cases. RESULTS: [AFP]/[hCG] ratio medians were independent of body weight and maternal age. There was a significant difference in the [AFP]/[hCG] ratio when comparing trisomy 21 and euploid pregnancies at each week. This difference became greater with advancing gestational age (P < 0.01). CONCLUSION: There is a significant difference in ratios of [AFP]/[hCG] between euploid and trisomy 21 pregnancies, which may be used to improve detection rates of Down syndrome screening.

The intra-aortic cannula pump: A novel assist device for the acutely failing heart.

OBJECTIVE: The intra-aortic cannula pump is a catheter pump designed to support the acutely failing heart. It expels blood from the left ventricle into the ascending aorta in a pulsatile flow pattern. The aim of the study was to analyze the hemodynamic performance of this new intracardiac support system in acute heart failure. METHODS: A 24F cannula was studied in a series of 16 sheep. Hemodynamic changes were assessed in the nonfailing, the moderately failing, and the severely failing heart. Heart failure was induced by an injection of microspheres into the left anterior descending coronary artery. The cannula was inserted through the aortic arch and introduced through the aortic valve into the left ventricle. RESULTS: Cannula insertion was feasible in all animals. Flow through the intra-aortic cannula flow was increased to a maximum of 3 L/min. No hemodynamic changes were observed in the nonfailing heart. A significant increase in cardiac output was observed in the moderately and severely reduced left ventricle (2.67 +/- 0.7 L to 3.51 +/- 0.83 L; P =.001; and 1.18 +/- 0.77 L to 2.43 +/- 0.44 L; P =.001, respectively). A drop in left atrial pressure was achieved in moderate and severe heart failure (14.1 +/- 5.93 mm Hg to 9.71 +/- 2.63 mm Hg; P =.0001; and 23 +/- 7.16 mm Hg to 11.2 +/- 2.55 mm Hg; P = 0.0001, respectively). Systolic and diastolic systemic blood pressures increased in the severely failing heart (57.3 +/- 12.8 mm Hg to 75.4 +/- 11.2 mm Hg; P =.0001; and 35.6 +/- 8.2 mm Hg to 60 +/- 14.3 mm Hg; P =.0006, respectively). CONCLUSIONS: Hemodynamic data demonstrate the beneficial effects of the intra-aortic cannula pump in moderate and severe heart failure. The intra-aortic cannula pump represents a new modality for the treatment of acute heart failure.

Hemodynamic changes and right heart support during vertical displacement of the beating heart.

BACKGROUND: Hemodynamic instability during heart displacement in off-pump multivessel coronary artery bypass grafting might be related to right heart dysfunction. The Enabler (HemoDynamics Systems Ltd, Upper Yoqneam, Israel) is a cannula pump that expels blood from the right atrium into the pulmonary artery. We studied the hemodynamic changes and the role of the enabler during heart displacement. METHODS: Nine anesthetized sheep were assessed for hemodynamic changes during 90-degree heart displacement with or without Enabler support. Hemodynamic parameters included cardiac output, systemic arterial blood pressures, and left and right heart filling pressures. RESULTS: Heart displacement caused a significant decrease in cardiac output and systemic blood pressure (46%+/-5%, p = 0.001; and 20%+/-5%, p = 0.009, respectively), with a concomitant 137%+/-24% (p = 0.003) increase in central venous pressure. No significant change in left atrial pressure was observed. Activation of the Enabler caused a significant increase in cardiac output and systemic blood pressure (67%+/-15%, p = 0.01; and 17%+/-7%, p = 0.04, respectively), as well as a decrease in central venous pressure by 49%+/-8% (p = 0.0001). CONCLUSIONS: Heart displacement causes hemodynamic instability mainly by right heart dysfunction. The Enabler significantly stabilized circulation during vertical displacement of the beating heart.

Novel thermoregulation system for enhancing cardiac function and hemodynamics during coronary artery bypass graft surgery.

BACKGROUND: Myocardial ischemia, arrhythmias, and coagulopathies are associated with postoperative hypothermia. This study assessed the efficacy of a novel thermoregulation system in alleviating these events during coronary artery bypass graft (CABG) surgery. METHODS: Elective CABG surgery patients were randomized into either Allon thermoregulation (AT, n = 40) or routine thermal care (RTC, n = 20) groups in whom the maintenance of normothermia during the nonbypass phases of the operation was compared. The AT used patients' rectal temperature as reference data to monitor the maintenance of the water temperature circulating at 37 degrees C in a garment. Rectal temperature, patient hemodynamics, and cardiac-specific troponin I (cTnI) levels were assessed at the induction of anesthesia, 30 minutes into surgery, at discontinuation of bypass, end of surgery, and 2 hours postoperatively. RESULTS: Body temperature was higher in the AT group compared to the RTC group at all five time points. Cardiac index (CI) (L/min) was higher in the AT group, 2.5 +/- 0.5, 2.6 +/- 0.5*, 3.2 +/- 0.6*, 3.3 +/- 0.5*, 3.1 +/- 0.7 at the respective time points, compared to the RTC group, 2.3 +/- 0.6, 2.1 +/- 0.2, 2.6 +/- 0.7, 2.7 +/- 0.7, 2.7 +/- 0.7 (*p < 0.05). Systemic vascular resistance (SVR) (dyne x s)/cm5) was consistently lower in the AT patients. Enzyme levels were elevated in both groups but were less so in the AT patients. CONCLUSIONS: The AT system can efficiently maintain normothermia. The beneficial effects are expressed by reduced SVR, elevated CI, and lower levels of cTnI, which may show a possible attenuation of myocardial injury.

Using a video conference to teach clinical clerks in a one-week cardiothoracic clerkship.

BACKGROUND: Students report that their operating room experience during specialty clerkships has been less than satisfactory. To deal with this and other problems in a 1-week cardiothoracic clerkship, a video conference system was introduced. METHODS: Three teaching strategies were used: a seminar dealing with the disease process and a description of the operative procedure; bedside pre-operative assessment of the patient, with a tutor; and a live video conference of the operation. The tutor observed the live video presentation with the students, initiating interaction with the operating surgeon and facilitating questions and discussion. Video quality was maintained by one camera connected to the headlight of the surgeon and another placed above the operative field. RESULTS: Both students and staff expressed a high degree of satisfaction in debriefing sessions and on a standard faculty evaluation form. CONCLUSIONS: This innovation in surgery specialty teaching contributes to the acquisition of educational objectives in the operating room and in a cardiothoracic clerkship.

Bicarbon valve -- European multicenter clinical evaluation.

OBJECTIVE: Fifteen collaborating centers in eight countries present their pooled experience with the new Bicarbon bileaflet valve. METHODS: Between 4/90 and 4/96, 1351 patients, 806 males and 545 females, aged 10 to 83, mean 58.4 +/- 12.4, underwent valve implantation. OPERATIONS: aortic valve replacement (AVR), 726; mitral valve replacement (MVR), 475; double valve replacement (DVR), 150. Additional procedures: CABG, 211; TV repair, 64; other, 152. RESULTS: Mortality: 67 early (seven valve related) and 56 late (40 valve related). Valve thrombosis: six obstructive, three non-obstructive; embolism: nine major cerebral, 37 other. Major bleeding: 29. Hemolysis: two clinically significant. Non-structural dysfunction: 24 paravalvular leaks, one leaflet interference. No structural failure! Endocarditis: 24. Reoperation 48: 22 non-structural dysfunctions, 14 endocarditis, seven thrombosis and embolism, five other. Estimated 5-year freedom from valve-related deaths is 97.2% for AVR and 92.4% for MVR; 4-year freedom from valve related deaths for DVR is 90.5%. Mean calculated NYHA improvement is 1.24. CONCLUSIONS: The Bicarbon mechanical prosthesis is well designed, durable, has good hemodynamic features and an acceptably low incidence of complications.

Identification of fetal problems associated with anticonvulsant usage and maternal epilepsy.

This article reviews the general approach for assessing teratogenic risks related to fetal exposure, concentrating on the specific patterns associated with anticonvulsant usage and maternal epilepsy. Major anomalies that might be detected prenatally are presented, as well as the patterns of minor anomalies (syndromes) that might be detected at birth or later. Each of the specific drugs used in the treatment of epilepsy is reviewed in detail. In addition, recent information concerning genetically determined variations in the metabolism of antiepileptic drugs is discussed in light of how genetic factors might relate to teratogenicity.

Low maternal serum concentrations of human chorionic gonadotropin as part of the triple test screening: a follow-up study.

OBJECTIVE: To determine whether low maternal serum concentrations of human chorionic gonadotropin (hCG) were associated with poor pregnancy outcome. METHODS: Between 1999 and 2000, 20,880 women underwent triple test screening in our hospital. The levels of hCG were detected by fluorescent immunoassay. Low hCG levels (< or = 0.20 MoM in our center) were considered to be a marker for increased risk for trisomy 18 or adverse pregnancy outcome. Each patient completed a questionnaire regarding fetal karyotype, complications of pregnancy and pregnancy outcome. RESULTS: Low maternal serum concentrations of hCG were detected in 119 pregnancies (0.57%). Of these, 19 (16%) were found to be missed abortions. The distribution of the remaining 100 cases was as follows: 72% had an isolated low hCG level, 24% had a low hCG level and a combination of hCG + alpha-fetoprotein < 0.80 MoM, and 4% had a low hCG level and a combination of hCG + unconjugated estriol < 0.80 MoM. No trisomy 18 or other chromosomal abnormalities were detected in our patient population. However, there were perinatal complications. CONCLUSION: Based on our screened population, a combination of multiple analytes seemed to be a better marker than an isolated finding of low maternal serum concentrations of hCG with regards to abnormal fetal karyotype, specifically trisomy 18, although it did determine a high-risk group in terms of complications of pregnancy.

Video assisted thoracic surgery: our experience with 102 patients.

UNLABELLED: Recent advances in optics, video systems and endoscopic operating instruments have made thoracoscopy easier and more accurate. From May 1992 until December 1993 we performed 102 Video Assisted Thoracic Surgical Procedure (VATS) for diagnosis and treatment. Twenty patients underwent thoracoscopy, twelve had pleurodesis. Seventy operative thoracoscopies included pulmonary wedge resection, dorsal sympathectomy, management of empyema, pleural tumor, bullectomy, pericardial window, anterior release for kyphoscoliosis and resection of posterior mediastinal cyst. In most cases of parenchyma resection, it was necessary to use three ports: one for video-endoscopy and two for preparation instruments and stapler. The average operation time was 58 minutes and average hospital stay was 3.5 days. Four patients died within 30 days after the procedure due to multi-organ failure, end-stage malignant disease and post pneumonectomy pulmonary edema, unrelated to the VATS itself. One patient had thoracotomy due to uncontrolled bleeding. No wound infection or other postoperative complication except intercostal neuralgia after dorsal sympathectomy was noticed. Localization of the target lesion deep within the parenchyma of the lung still poses a problem. We used a small incision (2 cm long), placing a finger to directly palpate the lung and locate the lesion, or made a mini thoracotomy. Conversion to thoracotomy was performed when malignancy was demonstrated at frozen section. CONCLUSIONS: 1) Thoracoscopy is a minimally invasive surgical technique causing a low morbidity rate and attaining a high diagnostic accuracy. 2) Postoperative recovery is brief and uneventful. New techniques of imaging are needed to locate the target lesion.

Comparison of endometrial pathologies collected by hysteroscopy and hysterectomy in postmenopausal breast cancer tamoxifen-treated patients.

PURPOSE OF INVESTIGATION: 1) To assess whether endometrial specimens obtained from removed uteri might show an increase in endometrial pathologies which had been previously diagnosed by hysteroscopy in postmenopausal breast cancer tamoxifen-treated patients. 2) To assess whether hysteroscopy is an efficient method of detecting endometrial pathologies in such patients. METHODS: The findings of two consecutive pathological evaluations in 18 postmenopausal breast cancer tamoxifen-treated patients, performed 11.2+/-11.2 months apart, were compared. The first specimen was collected by hysteroscopy and the second was obtained following hysterectomy. RESULTS: The most significant changes observed were three new cancers diagnosed at hysterectomy, one of which was poorly-differentiated. In the first (hysteroscopy) samplings, one patient had atrophic endometrium, a second patient had endometrial proliferation and a third patient had a benign endometrial polyp. Overall, 55.6% of the study patients had various endometrial pathologies in the first sampling, while 83.3% had endometrial pathologies in the second sampling. However, this difference was not statistically significant. CONCLUSION: 1) Endometrial histologic evaluations, performed on removed uteri 11.2+/-11.2 months following previous endometrial samplings of postmenopausal breast cancer tamoxifen-treated patients, showed a non-significant risk of developing overall endometrial pathologies. 2) Hysteroscopy may have missed some endometrial pathologies which were diagnosed later on in specimens obtained by hysterectomy.

[Muscle-sparing thoracotomy: a renewed approach in thoracic surgery].

Lateral thoracotomy has been the traditional approach in general thoracic surgery for several decades, and with anterior and posterior extension, gives excellent exposure for almost all intrathoracic procedures. However, division of the chest wall muscles, usually with diathermy, contributes to prolonged pain and morbidity. A muscle-sparing thoracotomy which preserves chest wall muscles and gives adequate exposure has been used by us for the past 2 years as an alternative to the standard thoracotomy.

[Videothorascopic sympathectomy (VATS) for palmar hyperhidriosis:summary of a clinical trial and surgical results].

Palmar hyperhidriosis is not a life-threatening disease but leads to loss in the quality of life. Conservative treatment is ineffective and major surgery involves perioperative complications and esthetic impairment. From 1992 to 1998 we treated 156 patients with palmar hyperhidriosis using a single port, drainless videothoracoscopic procedure with almost no complications.

[Video-assisted thoracic surgery--experience with 586 patients].

Recent advances in optics, video systems and endoscopic operating instruments have led to increasing application of thoracoscopic surgery, as it has become easier to perform and more accurate. We performed 586 video-assisted thoracic surgical procedures for diagnosis and treatment (May 1992-Dec. 1998) 127 were for diagnostic thoracoscopy and 79 for pleurodesis. 380 cases of operative thoracoscopy included pulmonary wedge resection (for interstitial lung disease, benign and malignant pulmonary tumors and pulmonary metastases) bullectomy, management of empyema, pleural tumor biopsy, thoracic sympathectomy, pericardial window formation, thoracic spinal procedures and resection of posterior mediastinal cysts. Recently we have had good experience in evacuating blood and blood clots from the thorax which accumulated after cardiac and thoracic surgery. Patients were placed in the lateral thoracotomy position and were ventilated with a double-lumen endotracheal tube, enabling collapse of the operated lung. The operating approach was through 1-3 thoracic ports. Mean operation time was 55 minutes, chest-tubes remained for 2.2 days (mean) and mean hospitalization was 3.3 days. There were no wound infections or significant postoperative complications. 5 patients had air leaks longer than 7 days; none required further surgical intervention. There was intercostal neuralgia and Horner's syndrome after thoracic sympathectomy (1 each) In cases in-which localizing the parenchymal lesion was difficult, the lung was palpated directly by inserting a finger through a small incision or a mini-thoracotomy. Conversion to thoracotomy was performed when primary malignancy of lung was diagnosed by frozen section. Only 2 patients had thoracotomy for uncontrolled bleeding. Thoracoscopy is a minimally invasive surgical technique with very low morbidity and high diagnostic accuracy. Postoperative recovery is brief and uneventful.

Ischaemia or reperfusion: which is a main trigger for changes in nitric oxide mRNA synthases expression?

OBJECTIVE: To investigate alterations in endothelial nitric oxide synthase and inducible nitric oxide synthase mRNA expressions and nitric oxide release in the myocardium during ischaemia/reperfusion and determine whether these changes are ischaemic and/or reperfusion dependent. MATERIALS AND METHODS: Isolated rat hearts were perfused by a modified Langendorff system. Following 1 h of global cardioplegic ischaemia, left ventricle haemodynamic parameters were recorded at baseline and during 30 min of reperfusion. Levels of endothelial, inducible nitric oxide synthases mRNA expression and nitric oxide release were measured at baseline, after ischaemia and at 30 min of reperfusion. RESULTS: Global cardioplegic ischaemia caused a significant depression of left ventricular function and a decrease of coronary flow. Postischaemic intensities of the endothelial nitric oxide synthase mRNA bands were significantly lower than at baseline (P < 0.01). There were no significant differences in endothelial nitric oxide synthase mRNA band intensities immediately after ischaemia compared to the end of reperfusion, nor between the intensities of inducible nitric oxide synthase mRNA bands at baseline, at end of ischaemia and at end of reperfusion. Nitric oxide in the myocardial effluent was below detectable levels at all measured points. CONCLUSION: Ischaemic injury causes down-regulation of endothelial nitric oxide synthase mRNA expression, which is then associated with reduction of coronary flow during reperfusion, representing one possible mechanism of ischaemia/reperfusion injury. We did not find expected elevations of inducible nitric oxide synthase mRNA expression during ischaemia or reperfusion and we suggest that ischaemia/reperfusion injury is not associated with nitric oxide overproduction.

Fetal choroid plexus cysts--is a genetic evaluation indicated?

A study of the association between aneuploidy and fetal choroid plexus cysts (CPCs) is presented. By reviewing the world prospective and retrospective studies, one cannot reach an agreed conclusion since different study designs were used and meta analysis is not feasible. Our experience is that as a solitary ultrasonographic finding, genetic evaluation is not indicated in cases of CPC. However, all the 'risk factors' of fetal aneuploidy such as maternal age, biochemical markers, and ultrasonographic signs may create a score by which the indication for genetic evaluation will be more sound.