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Abstract: The concurrent background level of metabolic activity may control state of vigilance, promoting wakefulness (and hunger) when it is low, or sleep (and satiety) when it is high. In a series of experiments, we have shown that sleep is dependent on feeding, but only because of the metabolic consequences of food ingestion. These consequences are sensed by glioneuronal populations (at least in the rostromedial hypothalamus), which probably respond to channel-bound adenosine triphosphate/diphosphate turnover (ischymetric monitoring) rather than to the binding of such downstream molecules as adenosine and cytochrome c oxidase. This basic signal is communicated to the vigilance-controlling centers by a cascade of peptidic and nonpeptidic messengers—messengers that promote wakefulness and hunger, possibly via a hypometabolic action (as in the case of neuropeptide Y or hypocretins), or somnolence and satiety, possibly via a hypermetabolic action (as in the case of leptin or certain serotonergic agents). [Copyright &y& Elsevier]

A prospective molecular epidemiology study of HIV-1 infection was conducted in newly diagnosed and antiretroviral-naive patients in Northern Greece between 2009 and 2010 using a predefined enrolling strategy. Phylogenetic trees of the pol sequences obtained in this study with reference sequences indicated that subtypes B and A1 were the most common subtypes present and accounted for 44.9% and 42.9%, respectively, followed by subtype C (3.1%), CRF02_AG (4.1%), CRF04_cpx (2.0%), and subtypes CRF01_01, F1, and G (1.0%). A high rate of clustered transmission of subtype A1-resistant strains to reverse transcriptase (RT) inhibitors was observed among men having sex with men. Indeed, 15 out of 17 study subjects (88.2%) infected with transmitted drug resistance (TDR) strains were implicated in transmission clusters, 10 of whom (66.7%) were men who have sex with men (MSM), and were also infected with subsubtype A1 strains. The main cluster within subtype A1 (I) included eight men reporting having sex with men from Thessaloniki infected with dual-class RT-resistant strains carrying both T215C and Y181C mutations.

The emergence of resistance against current antiretroviral drugs to human immunodeficiency virus type 1 (HIV-1) is an increasingly important concern to the continuous success of antiretroviral therapy to HIV-1-infected patients. In the past decade, a number of studies reported that the prevalence of transmitted drug resistance among newly diagnosed patients has reached an overall 9% prevalence worldwide. Also, a number of studies using longitudinal HIV-1 patient study cohorts demonstrated that the cellular HIV-1 DNA level in peripheral blood mononuclear cells (PBMCs) has a prognostic value for the progression of HIV-1 disease independently of plasma HIV-1 RNA load and CD4 count. Using a previously established molecular-beacon-based real-time PCR methodology, cellular HIV-1 DNA levels were quantified in newly diagnosed and antiretroviral-naive patients in Northern Greece recruited between 2009 and 2010 using a predefined enrolling strategy, in an effort to investigate whether there is any relationship between cellular HIV-1 DNA levels and HIV-1 transmitted drug resistance. As part of the same study, DNA sequences encoding the env (C2-C5 region of gp120) were also amplified from PBMC-extracted DNA in order to determine the genotypic coreceptor tropism and genetic subtype. Cellular HIV-1 DNA levels had a median of 3.309 log10 HIV-1 copies per 10(6) PBMCs and demonstrated no correlation between cellular HIV-1 DNA levels and HIV-1 transmitted drug resistance. An absence of association between cellular HIV-1 DNA levels with plasma viral HIV-1 RNA load and CD4 levels was also found reconfirming the previously published study. Genotypic analysis of coreceptor tropism indicated that 96% of samples, independently of the presence or not of genotypic drug resistance, were CCR5-tropic. Overall, the findings reconfirmed the previously proposed proposition that transmitted drug resistance does not have an impact on disease progression in HIV-1-infected individuals. Also, CCR5 coreceptor tropism dominance suggests that both drug-resistant and drug-sensitive strains behave similarly in early infection in newly diagnosed patients.

In homozygous beta-thalassemia, the organ damage is mainly attributed to excessive iron deposition through the formation of oxygen free radicals. Despite appropriate transfusion and chelation therapy and low ferritin levels, patients still develop organ failure, heart failure being the main cause of death. This study was designed to determine whether the decreased antioxidant activity of the apolipoprotein E (APOE) 4 allele could represent a genetic risk factor for the development of left ventricular failure (LVF) in beta-thalassemia homozygotes. A total of 251 Greek beta-thalassemia homozygotes were studied. Patients were divided in three groups: group A (n = 151) with no cardiac impairment, group C (n = 47) with LVF, and 53 patients with LV dilatation and normal LV systolic function constituted the group B. DNA was obtained from all patients, and the polymerase chain reaction was used to analyze the polymorphism at the APOE locus. The APOE allele frequencies were compared with those of a Greek control sample of 216 healthy blood donors. Patients with no cardiac impairment had an APOE 4 allele frequency (7.9%) not different from population controls (6.5%, P > .05), while patients with LVF had a significantly higher frequency of APOE 4 (12.8%) than the controls (P < .05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32). The APOE 4 allele may represent an important genetic risk factor for the development of organ damage in homozygous beta-thalassemia., (Copyright 1998 by The American Society of Hematology)

Causes of chromosomal nondisjunction is one of the remaining unanswered questions in human genetics. In order to increase our understanding of the mechanisms underlying nondisjunction we have performed a molecular study on trisomy 8 and trisomy 8 mosaicism. We report the results on analyses of 26 probands (and parents) using 19 microsatellite DNA markers mapping along the length of chromosome 8. The 26 cases represented 20 live births, four spontaneous abortions, and two prenatal diagnoses (CVS). The results of the nondisjunction studies show that 20 cases (13 maternal, 7 paternal) were probably due to mitotic (postzygotic) duplication as reduction to homozygosity of all informative markers was observed and as no third allele was ever detected. Only two cases from spontaneous abortions were due to maternal meiotic nondisjunction. In four cases we were not able to detect the extra chromosome due to a low level of mosaicism. These results are in contrast to the common autosomal trisomies (including mosaics), where the majority of cases are due to errors in maternal meiosis.

Chromosomal aneuploidy is one of the major causes of pregnancy wastage. In this review we summarize the knowledge about the origin and mechanisms of non-disjunction in human autosomal trisomies 8, 13, 15, 16, 18, and 21, accumulated during the last decade by using DNA polymorphism analysis. Maternal meiosis I non-disjunction is the most important single class, but chromosome-specific patterns exist. For the acrocentric chromosomes 15 and 21, meiosis I errors predominate among the maternal errors, in contrast to trisomy 18 where meiosis II errors predominate. For trisomy 16, virtually all cases are due to maternal meiosis I non-disjunction. Postzygotic (mitotic) non-disjunction constitutes 5-15% of cases of trisomies 15, 18, and 21, whereas for trisomy 8 and trisomy 8 mosaicism the majority of cases are due to mitotic non-disjunction. For paternal non-disjunction of chromosomes 18 and 21, meiosis II or mitotic errors predominate. There is aberrant meiotic recombination associated with maternal meiotic non-disjunction in all trisomies studied in detail so far. Advanced maternal age remains the only well documented risk factor for maternal meiotic non-disjunction, but there is, however, still a surprising lack of understanding of the basic mechanism(s) behind the maternal age effect.

Objectives: In fetuses with a single umbilical artery the entire blood flow to the placenta is transported through the common and internal iliac arteries from the side of the single artery, whereas the pelvic vessels from the side of the missing artery do not participate in the fetoplacental circulation. The aim of this study was to investigate the effect of gestational age on pelvic arterial blood flow in fetuses with single umbilical artery., Design: In 15 fetuses with a single umbilical artery (SUA), common iliac artery flow velocity waveforms were studied longitudinally using high resolution colour Doppler ultrasonography at three gestational ages: 18 to 20 weeks, 28 to 30 weeks, and 35 to 37 weeks. The pulsatility index was measured in each common iliac artery and mixed model analysis of variance was used to examine the effect of gestational age and side., Results: There was a highly significant difference in pulsatility index between common iliac arteries at all gestational ages, the values always being higher on the side that did not participate in the fetoplacental circulation (P < 0.001). For increasing gestation, the pulsatility index fell significantly in the SUA side but remained high in the non-SUA side (P < 0.001)., Conclusions: This study shows that the asymmetry in the pelvic arterial blood flow in fetuses with SUA increases as pregnancy progresses, consistent with decreasing vascular resistance in the placenta and increasing resistance in the lower extremities.

Objective: Our purpose was to determine whether the presence of heme pigments in amniotic fluid is associated with the ultrasonographic findings of increased fetal bowel echogenicity in the second trimester., Study Design: Spectrophotometric analysis of amniotic fluid for optical density at 410 nm was prospectively performed to study the presence of heme pigments in (1) 104 pregnancies undergoing second-trimester amniocentesis for routine cytogenetic indications and (2) in 14 pregnancies undergoing amniocentesis for prenatal karyotyping because of fetal strongly echogenic bowel. In the routine amniocentesis group the fetal small bowel echogenicity was assessed immediately before amniocentesis and classified as nonechogenic (n = 64), mildly echogenic (n = 36), or hyperechogenic (n = 4) with the fetal iliac wing and liver used as references. Only amniotic fluid specimens that were obtained at the first attempt and that were not blood-stained were included in this study, with the first milliliter being discarded in all samples., Results: In the routine amniocentesis group abnormal amniotic fluid optical density readings were significantly more frequent in fetuses with increased bowel echogenicity compared with those with nonechogenic bowel (8/40 [20%] vs 3/64 [5%], respectively; p < 0.001). In the hyperchogenic bowel group abnormal amniotic fluid optical density readings were found in four samples (29%). Overall, 12 of 54 fetuses (22%) with increased bowel echogenicity had a detectable peak at 410 nm. Three of the 12 (25%) fetuses with echogenic bowel and positive readings for hemoglobin were chromosomally abnormal., Conclusions: Fetal small bowel echogenicity is associated with the presence of heme pigments in amniotic fluid as determined by amniotic fluid optical density at 410 nm. Swallowing of amniotic fluid after intraamniotic bleeding seems implicated in the etiology of second-trimester echogenic bowel in both euploid and aneuploid fetuses.

Hyperechogenic bowel has been described as a normal variant in second-trimester fetuses, but also in association with cystic fibrosis, chromosomal abnormalities, congenital infection, intestinal obstruction and intra-amniotic bleeding. These fetuses are also at risk for poor perinatal outcome, mainly due to intrauterine growth retardation. In this report we examine the potential of ultrasonographic detection of isolated fetal hyperechogenic bowel in the second trimester as a marker of subsequent suboptimal fetal growth. Second-trimester fetuses with hyperechogenic bowel in comparison to controls had a greater incidence of birth weight below the 10th centile (6/48, 12.5% vs. 4/149, 2.7%, respectively; p = 0.01) and lower mean birth weight (3176 g (SD 741 vs. 3499 g (SD 493)), respectively; p = 0.001). There was no difference in the prevalence of preterm delivery in both groups (3/48, 6.3% vs. 8/149, 5.4%, respectively; p = 0.7). This study suggests that second-trimester fetuses normally-grown with isolated hyperechogenic bowel are at risk for suboptimal fetal growth.

The fetal gall bladder can now be easily identified during the second and third trimesters using high-resolution ultrasonography. In this report we present eight fetuses with an enlarged gall bladder detected on prenatal ultrasonography at a mean gestational age of 24.6 weeks (range 19-31 weeks). Additional ultrasonographic findings were present in four cases: fetal anomalies and intrauterine growth retardation in three and polyhydramnios in one. Of those cases associated with fetal anomalies, one women underwent amniocentesis at 21 weeks revealing trisomy 18. The other two declined prenatal karyotyping; neonatal karyotyping revealed trisomy 13 in one and trisomy 18 in the other. Although an enlarged fetal gall bladder can be a normal variant in the second and third trimesters, the prenatal detection of cholecystomegaly should prompt a search for associated anomalies and other markers of aneuploidy. If found, prenatal karyotyping should be considered.

We examined retrospectively the use of ultrasonography in 18 cases in which a true knot of the umbilical cord was found at delivery. All women had a normal second-trimester scan in which no cord abnormality was detected. Thirteen (72%) also had third-trimester color Doppler ultrasonography, at which time the cord anomaly was again missed. In one of these cases the diagnosis could have been made with color flow imaging, but the abnormal pattern was mistaken instead for multiple loops of cord. On the other hand, the diagnosis of true knot was considered prenatally in two cases, but not confirmed at delivery, when only a prominent false knot was found in one and a normal cord in the other. We conclude that true knots of the umbilical cord do not have a characteristic appearance in utero and therefore are easily missed at routine prenatal ultrasonography.

In 52 women in late pregnancy, the mean durations of transient fetal tachycardia after vibroacoustic stimulation during low fetal heart rate variability (4.8 minutes) and high fetal heart rate variability (6.3 minutes) were similar. The fetal heart rate continued with high variability in all cases, suggesting that the fetus did not return to its prestimulation state after vibroacoustic stimulation during quiescence. In 10 women, the duration of high variability after vibroacoustic stimulation during low fetal heart rate variability was significantly shorter (mean, 22 minutes) than the preceding (mean, 36 minutes) or subsequent (mean, 43 minutes) high-variability components of complete rest activity cycles. In another 10 women, the duration of high variability after vibroacoustic stimulation during high fetal heart rate variability was similar to preceding and subsequent high-variability episodes. In these 20 women, the next complete rest-activity cycle after vibroacoustic stimulation was not different in duration to the complete cycle recorded on the previous day.

The liver enzymes, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP), were measured in the blood of 25 fetuses with severe Rh alloimmunization at the time of their first, second and third intravascular transfusions and in 17 comparison fetuses. In the comparison group, GGT increased with advancing gestation (r = 0.7; P = 0.002), whereas ALP, AST and ALT did not correlate with gestational age. Rh hydropic fetuses (n = 8) had higher blood ALT levels than the comparison fetuses (P = 0.008) had significantly increased transaminases when compared with non hydropic fetuses (n = 17). In hydropic fetuses, AST correlated with the nucleated red cell count before transfusion (r = 0.94; P = less than 0.0001). Fetal transaminases were no longer increased in hydropic fetuses by the second (AST) or third (ALT) transfusion. In both hydropic and non hydropic fetuses, GGT increased by the second transfusion (median percentage change +85%, range -83% to +596%; P = 0.003). The rise in fetal GGT was transitory and correlated with the increase in fetal haematocrit at the first transfusion (r = 0.58; P = 0.006). This study reports liver dysfunction secondary to extramedullary erythropoiesis in Rh alloimmunization and implicates portal hypertension for the rise in fetal GGT with transfusion.

The safety of vibroacoustic stimulation (VAS), which produces marked changes in fetal heart rate, movements and behavioural state, remains unclear. In order to determine whether VAS is associated with catecholamine release, we measured plasma noradrenaline and adrenaline in 13 appropriately grown normoxaemic fetuses between 28 and 40 weeks gestation immediately before and 60 and 75 s after VAS. Over this time interval, VAS is known to increase fetal heart rate. There was no significant change in either noradrenaline (median change = +0.06 ng/ml, P = 0.26) or adrenaline levels (median change = +0.03 ng/ml, P = 0.4). This study suggests that sympathoadrenal activation is not part of the fetal response to VAS. These findings do not support the recent suggestion that VAS may be deleterious to the fetus by provoking sudden release of catecholamines.

Fetal acid-base status was evaluated on 66 blood samples taken for rapid karyotyping from 58 growth-retarded fetuses. Before blood sampling, doppler blood flow studies of the umbilical artery showed end-diastolic frequencies to be absent in 32 fetuses (group 1) and present in 26 (group 2). Fetuses with chromosomal (n = 4) or structural (n = 8) abnormalities were excluded from subsequent analysis. Gestational age at blood sampling (27.8 [95% CI 26.5-29.1] vs 32.2 [30.4-34.1] weeks) and time from sampling to delivery (median 2 (range 0-35] vs 14 [0-77] days) were significantly lower in group 1 than group 2. There were no perinatal deaths in group 2 whereas mortality in group 1 was 65.4%. There were significant differences between the groups at blood sampling in pH, pO2, pCO2, base equivalents, and nucleated-red-cell count, but within group 1 these measurements were similar in surviving fetuses and those who died perinatally. Since acid-base determination does not predict perinatal outcome in growth-retarded fetuses, fetal blood sampling has a limited role in monitoring fetal wellbeing.

Transabdominal fetal blood sampling under ultrasonic guidance was performed at the intrahepatic vein on 214 occasions in 177 fetuses. In 72 cases, an intravascular transfusion was also attempted at the same site. In 91.1% of the samplings, more than 1 mL of pure fetal blood was obtained, and in 89.9% of transfusions, fetal hematocrit or platelet concentration was raised to a satisfactory level. Fetal bradycardia and intraperitoneal bleeding occurred in 2.3% of the cases. Among fetuses at low risk, there was only one intrauterine death, which occurred 3 weeks after the procedure, and one spontaneous abortion in a patient with twin pregnancy. In fetuses with Rh/Kell alloimmunization or perinatal alloimmune thrombocytopenia, the survival rate was 86%. Four liver enzymes were assayed in the blood of 13 fetuses that underwent transfusions at the intrahepatic vein and 13 controls in whom the site of sampling was the umbilical vein at the placental cord insertion. No differences were found between the groups at the subsequent transfusion 2-5 weeks later. The intrahepatic vein is an alternate site of sampling/transfusion when access is difficult or failure occurs at the placental cord insertion. This approach minimizes the risks of fetal blood loss, fetomaternal hemorrhage, arterial vasospasm, and cord tamponade.

A case of hydrops fetalis caused by massive fetomaternal hemorrhage was initially successfully treated by intrauterine intravascular transfusion. Unexplained intrauterine death occurred 2 weeks afterwards. The investigation of fetomaternal hemorrhage by fetal blood sampling and the management are discussed.