CHIP, ICUS, CCUS and other four-letter words.

Clonal hematopoiesis can be identified by the presence of somatic mutations in blood or bone marrow even in individuals without a myeloid malignancy. Advances in DNA sequencing have led to the discovery that clonal hematopoiesis is remarkably common and occurs in a wide variety of settings, each often described by unique acronym. These distinctions can be useful as the implications of clonal hematopoiesis depend almost entirely on the clinical context in which it is identified. However, some generalizations can be made. The prevalence of clonal hematopoiesis increases with age, particularly after the fifth decade of life. Clonal hematopoiesis in normal individuals with very small clones is typically benign, while patients with clinically abnormal hematopoiesis, larger clones and more driver gene mutations appear to be at much greater risk. Understanding the significance of clonal hematopoiesis in the various contexts in which it occurs can influence how physicians assess risk, select therapies and counsel their patients. This concise review examines the implications of clonal hematopoiesis in several settings, including normal aging, aplastic anemia, unexplained cytopenias and patients receiving cytotoxic chemotherapy.

Toll-like receptor alterations in myelodysplastic syndrome.

Recent studies have implicated the innate immunity system in the pathogenesis of myelodysplastic syndromes (MDS). Toll-like receptor (TLR) genes encode key innate immunity signal initiators. We recently identified multiple genes, known to be regulated by TLRs, to be overexpressed in MDS bone marrow (BM) CD34+ cells, and hypothesized that TLR signaling is abnormally activated in MDS. We analyzed a large cohort of MDS cases and identified TLR1, TLR2 and TLR6 to be significantly overexpressed in MDS BM CD34+ cells. Deep sequencing followed by Sanger resequencing of TLR1, TLR2, TLR4 and TLR6 genes uncovered a recurrent genetic variant, TLR2-F217S, in 11% of 149 patients. Functionally, TLR2-F217S results in enhanced activation of downstream signaling including NF-κB activity after TLR2 agonist treatment. In cultured primary BM CD34+ cells of normal donors, TLR2 agonists induced histone demethylase JMJD3 and interleukin-8 gene expression. Inhibition of TLR2 in BM CD34+ cells from patients with lower-risk MDS using short hairpin RNA resulted in increased erythroid colony formation. Finally, RNA expression levels of TLR2 and TLR6, as well as presence of TLR2-F217S, are associated with distinct prognosis and clinical characteristics. These findings indicate that TLR2-centered signaling is deregulated in MDS, and that its targeting may have potential therapeutic benefit in MDS.

La discapacidad y su inclusion social: un asunto de justicia / The discapacity and their social inclusion: a matter of justice

Se plantea la relación entre la discapacidad y la justicia. Con base en la perspectiva política de John Rawls ante la discapacidad. La posición de éste autor es conceder a grupos minoritarios, en este caso a las personas con discapacidad, la maximización de los bienes sociales (empleo, ingresos, educación y salud entre otros) ya que su dotación en bienes primarios naturales y al azar es escasa o diferente (salud, talentos, y funcionamientos). El texto busca contribuir a la comprensión de la discapacidad desde la justicia ya que es lo que lleva a que el hombre pueda realizarse plenamente en cualquier ámbito. Reconoce que es prioritario que las instituciones elijan lo correcto para todos y no lo bueno para pocos. Se concluye que la discapacidad es una categoría moral - política y que es la justicia quien exigirá a las instituciones sociales, actores externos y entes gubernamentales (familia, comunidad, estado y sociedad) el reconocimiento y visibilidad de las personas con discapacidad como sujetos políticos

Towards cooperative frameworks for modeling and integrating biological processes knowledge.

Data organization has become a strategic target for biologists due to the increasing volume of genomic data available for them. For this purpose, we need a complete knowledge model for representing biological system. In this paper, we deal with both processes for the creation and integration of shareable, reusable domain models within biology, which is a critical issue. In particular, this work introduces a new cooperative development approach for biology ontologies. This approach is based on the integration of the ontologies supplied by different human experts. Two experiments in biological domains are presented and their results discussed.

Automated monitoring of medical protocols: a secure and distributed architecture.

The control of the right application of medical protocols is a key issue in hospital environments. For the automated monitoring of medical protocols, we need a domain-independent language for their representation and a fully, or semi, autonomous system that understands the protocols and supervises their application. In this paper we describe a specification language and a multi-agent system architecture for monitoring medical protocols. We model medical services in hospital environments as specialized domain agents and interpret a medical protocol as a negotiation process between agents. A medical service can be involved in multiple medical protocols, and so specialized domain agents are independent of negotiation processes and autonomous system agents perform monitoring tasks. We present the detailed architecture of the system agents and of an important domain agent, the database broker agent, that is responsible of obtaining relevant information about the clinical history of patients. We also describe how we tackle the problems of privacy, integrity and authentication during the process of exchanging information between agents.

The effect of autonomous alpha-CaMKII expression on sensory responses and experience-dependent plasticity in mouse barrel cortex.

The calcium/calmodulin kinase II (CaMKII) autophosphorylation site is thought to be important for plasticity, learning and memory. If autophosphorylation is prevented by a point mutation (T286A) LTP is blocked in the hippocampus and cortex. Conversely, if the point mutation mimics autophosphorylation (T286D) a range of frequencies that normally produce LTP in wild types cause LTD instead. In order to test whether the alphaCaMKII-T286D mutation increases levels of depression in vivo, we examined the effect of the alphaCaMKII-T286D transgene on plasticity induced in the barrel cortex by whisker deprivation. Surprisingly, the mutation did not affect depression or potentiation. However, in animals reared with the transgene turned on from birth, the surround receptive field responses were greater than normal. This effect may be due to the potentiating action of autophosphorylated CaMKII during early development.

Intact survival in extremely low birth weight infants after delivery room resuscitation.

OBJECTIVE: None of the 20 previously reported infants weighing <750 g at birth who received cardiopulmonary resuscitation (CPR) in the delivery room (DR) survived. To clarify whether such resuscitation is futile in our center, we evaluated our experience with DR-CPR over a 4-year period. STUDY DESIGN: We retrospectively reviewed the outcomes of all inborn infants with birth weights <1000 g at University of California, San Diego Medical Center from January 1993 to December 1996. Surviving infants and matched control infants were followed for /=750 g. Overall, 19 infants received DR-CPR, of whom 12 were <750 g. Of the infants who received DR-CPR, 79% (15/19) survived, including 10 of 13 infants <750 g and 5 of 6 infants >/=750 g. Of the 15 survivors, 10 were followed beyond 10 months' adjusted age (median: 28 months). At last examination, 70% were both neurologically and developmentally normal. Two infants had cerebral palsy with mild cognitive and severe motor developmental delay. Of 7 infants with birth weight <750 g, 6 had normal neurodevelopmental outcomes. The mean composite mental and motor scores of DR-CPR survivors were 93 +/- 10 and 89 +/- 25, respectively. No differences were found in neurologic or developmental outcome between DR-CPR survivors and control infants matched for gestational age, sex, and year of birth. CONCLUSIONS: Our results indicate that intact survival is possible for infants weighing <750 g at birth after DR-CPR.

Predictors of early childhood outcome in candidates for extracorporeal membrane oxygenation.

OBJECTIVE: To examine the effect of neonatal risk factors and treatment strategy on pulmonary, growth, and neurodevelopmental outcome of candidates for extracorporeal membrane oxygenation (ECMO). DESIGN: We prospectively assessed growth and neurodevelopmental outcome in a cohort of 190 neonates who had severe respiratory failure, no major congenital anomalies, and met institutional criteria for the use of ECMO. The relationships among perinatal risk factors, neonatal outcome, postnatal growth, and neurodevelopmental outcome were studied by univariate and multivariate analyses. RESULTS: Compared with 52 infants successfully treated with conventional or high-frequency ventilation, the 138 ECMO survivors were more mature, had earlier, more severe pulmonary disease, and were more likely to have meconium aspiration. The ECMO survivors had significantly fewer ventilator days (9 vs 11), hospital days (23 vs 29), and less (12% vs 25%) chronic lung disease (CLD). At 12 to 30 months, mean developmental scores of ECMO survivors were similar to those of infants who survived without ECMO. Infants with CLD had significantly lower motor scores (86 +/- 23 vs 100 +/- 19) and were more likely to have cerebral palsy (27% vs 6%) than those without CLD. The risk of adverse neurodevelopmental outcome was independently increased by CLD (odds ratio, 2.4; confidence interval, 1.2 to 4.6) and moderate or severe neonatal neuroimaging abnormalities (odds ratio, 6.4; confidence interval, 1.9 to 21.9). CONCLUSIONS: Neonatal ECMO candidates treated with ECMO did as well or better than neonates whose conditions were managed with alternate treatment strategies. Adverse neurodevelopmental outcome was predicted by moderate or severe neonatal neuroimaging abnormalities and CLD, not by treatment with ECMO.

High incidence of cranial ultrasound abnormalities in full-term infants with congenital heart disease.

The objective of this retrospective study was to determine the incidence and types of cranial ultrasound abnormalities in full-term infants with congenital heart disease (CHD). We reviewed the cranial ultrasound scans of 49 full-term infants with CHD and compared them to 42 healthy full-term control infants. The relationship of each abnormality with the type of CHD, the presence of cyanosis, and cardiac catheterization and cardiac surgery were examined. We found that infants with CHD had a higher incidence of cranial ultrasound abnormalities than control infants (59% versus 14%; p < 0.001). Cerebral atrophy and linear echodensities in the basal ganglia and thalamus were the most common sonographic findings in infants with CHD, particularly in those with coarctation of the aorta or ventricular septal defect. Intraventricular hemorrhage occurred more often in infants with acryanotic CHD than in those with cyanotic CHD. Cardiac catheterization and cardiac surgery had no significant effects on cranial ultrasound findings. We conclude that cranial ultrasound abnormalities are very frequent in full-term infants with CHD. These findings emphasize the importance of cranial ultrasonography and long-term neurodevelopmental follow-up of infants with CHD.

Placement of umbilical venous catheters with use of bedside real-time ultrasonography.

Real-time ultrasonography was used to assess the position of umbilical venous catheters tips in 79 newborn infants (birth weight range, 400 to 4200 gm). The position of the umbilical venous catheters determined by ultrasonography was compared with the projection of the catheter tip on the closest vertebral body shown on a standard chest radiograph. Of the catheters initially placed with radiographic guidance, 56% were repositioned because of unsatisfactory location. Ultrasonography is more precise than radiography because it allows direct visualization of the catheter tips in relation to internal vascular structures. When ultrasonography is unavailable, placement at the ninth thoracic vertebral body ensures safe positioning.

Effects on cerebral blood flow velocities of slow and rapid infusion of indomethacin.

In a randomized study, indomethacin was administered either by an intravenous rapid infusion or by a 30-minute intravenous infusion to preterm infants. Ten infants were randomly assigned to the rapid infusion group and nine to the other group. Time-averaged mean systolic, mean flow velocity, and mean diastolic blood flow velocities were measured in the internal carotid artery with a pulsed Doppler. Blood flow velocities, arterial blood gases, intraarterial blood pressures, and transcutaneous PO2 and PCO2 were measured at 5 and 1 minutes before indomethacin and then at 5, 10, 20, 30, 35, 40, 50, 60, and 90 minutes after indomethacin administration. Intravenous indomethacin either by rapid or slow infusion caused a significant decrease in the blood flow velocities. The blood flow velocities were significantly lower 5 minutes after rapid infusion and by 30 minutes in the slow-infusion group. In both groups, the blood flow velocities remained depressed up to 90 minutes. The blood pressures increased concomitantly to the blood flow velocities in the rapid-administration group only. Because indomethacin given for 30 minutes does not avoid the decrease in the blood flow velocities, further studies are necessary to ascertain the safest method of administration.

Confirmation of transpyloric feeding tube placement by ultrasonography.

We compared ultrasonography with radiography for placement of transpyloric feeding tubes. Ultrasound study successfully determined tube tip position and gave functional information unavailable with radiography, allowing for greater accuracy of placement and the observation of transpyloric reflux of feedings.

Electroencephalographic and neuroimaging findings in neonates undergoing extracorporeal membrane oxygenation.

Electroencephalograms (EEGs) were recorded on 36 infants who were treated with arteriovenous extracorporeal membrane oxygenation (ECMO) between 1986 and 1989. Twelve of 36 infants had EEGs prior to and during ECMO. Twenty-one infants who met ECMO criteria but were treated with mechanical ventilation only served as a comparison (COMP) group. Electrographic seizures occurred in 7 of the 36 (19%) ECMO patients and in 3 of the 21 (14%) COMP patients. Five of 7 ECMO infants had electrographic status epilepticus. Three infants developed electrographic seizures during ECMO in association with an acute cerebral injury. These patients did not have significant hemispheric predominance in the origin of electrographic seizures (2 right, 3 left and 2 bilateral). Repetitive or periodic discharges (RPD) with frequencies between 0.5 and 5 Hz were seen after starting therapy in 23 of the 36 (64%) ECMO patients and 15 of the 21 (71%) of the COMP group. Only in the ECMO patients did RPD arise significantly more frequently from the right hemisphere (13 right, 4 left and 6 bilateral; p = 0.015). Neuroimaging studies showed evidence of ischemic lesion in 8 of the 36 (22%) ECMO patients with significantly right-sided predominance (5 right, 1 left and 2 bilateral; p = .05). Cerebellar hemorrhages occurred in 3 ECMO patients. Ischemic lesions occurred in 3 of the 21 (14%) COMP patients, all occurring on the left side. In the ECMO group, severe outcome or death was significantly associated with the presence of electrographic seizures, status epilepticus, and suppression-burst pattern (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Outcome at twelve months of adjusted age in very low birth weight infants with lung immaturity: a randomized, placebo-controlled trial of human surfactant.

We compared the neurodevelopmental outcome of extremely premature, surfactant-deficient infants who received either prophylactic surfactant at birth, "rescue" surfactant after the clinical diagnosis of respiratory distress syndrome was established, or placebo. Infants studied were participants in a randomized, bicenter (San Diego, Calif., and Helsinki, Finland), controlled trial of human surfactant therapy. One hundred fifty infants (prophylaxis group, 63 infants; rescue group, 57; placebo group, 30) were prospectively enrolled at 38 weeks of gestational age. There were no neonatal intergroup differences in the incidence or severity of sonographic central nervous system abnormality or retinopathy. One hundred forty-five infants were alive at 1 year of adjusted age, at which time growth, neurosensory, and neurologic outcome were similar in all three treatment groups at both centers. Cerebral palsy occurred in 20% overall. Five infants (3.5%) were functionally blind. However, infants treated at birth had lower mean mental and motor scores on the Bayley Scales of Infant Development compared with those of infants rescued with surfactant after the onset of respiratory distress syndrome (Mental Development Index: 78 vs 96, p = 0.02; Psychomotor Development Index: 73 vs 87, p = 0.04). Chronic lung disease occurred more frequently in the prophylactically treated group and contributed to the subjects' neurologic and developmental morbidity. Because prophylactic surfactant treatment offered no neurodevelopmental advantage and may contribute to poorer outcome, we currently recommend early surfactant replacement only for those infants who have postnatal evidence of respiratory distress syndrome.

Postnatal white matter necrosis in preterm infants.

One hundred twenty-seven infants less than 36 weeks of gestation (mean +/- SE = 31 +/- 3.2 weeks) were studied with echoencephalography to determine the incidence and complications associated with white matter necrosis. Ten infants (8%) developed cysts ten or more days after birth, indicating postnatal onset of white matter necrosis. Univariate analysis showed that postnatal white matter necrosis was significantly associated with maternal infection (other than urinary infection), respiratory distress syndrome, and longer requirement of an oxygen concentration greater than 40%. Forward logistic regression analysis showed postnatal white matter necrosis to be associated with maternal infection, chronic placental infarction, congenital pneumonia, and longer requirement of an oxygen concentration greater than 40%. Neurodevelopmental outcome was abnormal during infancy in 4 of the 6 survivors with postnatal white matter necrosis. Severe respiratory disease and maternal and/or fetal infection appear to increase the risk of the immature brain to white matter necrosis, predisposing the infants to subsequent neurodevelopmental delay.

Internal carotid artery blood flow velocities before, during, and after extracorporeal membrane oxygenation.

Blood flow velocities in the internal carotid arteries were studied with pulsed Doppler in 25 neonatal patients (birth weight range, 2600 to 4100 g) who had extracorporeal membrane oxygenation (ECMO). Time averaged mean systolic, mean diastolic, and mean blood flow velocities were calculated. Five infants had right common carotid artery reconstruction. Blood flow velocities measured in 15 healthy full-term infants were used as controls. Findings during ECMO included the following: (1) forward flow in the right internal carotid artery in 50% of the infants; (2) significant increase in the mean diastolic and the mean flow velocities (48% and 128%, respectively) in the left internal carotid artery when compared with pre-ECMO and control infants' values; (3) the elevation in the mean and the mean diastolic velocities was associated with changes in the PaCO2 and with an increase in the diastolic blood pressure; and (4) forward blood velocities in the right internal carotid artery were comparable with blood velocities in the left internal carotid artery and with the blood velocities of control infants. After ECMO, the mean diastolic velocity in the left internal carotid artery decreased significantly, but it remained elevated when compared with pre-ECMO values. Infants with right common carotid reconstruction had blood velocities in the right internal carotid artery comparable with the simultaneous blood velocities in the left internal carotid artery and to the blood velocities of control infants. Twenty-eight percent of the infants had major neuroanatomic lesions. Right or left preponderance was not noted. No association between blood velocity values in the internal carotid arteries or flow direction and the presence or the absence of brain lesions was noted.

Carotid artery reconstruction following neonatal extracorporeal membrane oxygenation.

Although reconstruction of the right common carotid artery (RCCA) in neonatal extracorporeal membrane oxygenation (ECMO) patients is intuitively attractive, there is little known about prolonged arterial cannulation and how it may affect subsequent vascular repair. A histological study of RCCA segments from neonatal ECMO patients was performed, so that cannulation technique and catheter design could be optimized before proceeding with arterial reconstruction. Circumferential transmural necrosis (CTN) was found in 25 of 31 (80%) arteriotomy specimens in comparison with 2 of 9 (20%) more proximal carotid specimens; the remaining specimens in each group demonstrated either focal subintimal or focal transmural necrosis. CTN was more common in patients with longer ECMO runs (96 +/- 5.9 versus 75 +/- 5.6 hours, P = .009; arteriotomy site), but was independent of cannula size, birthweight, and gestational age. Eleven patients have undergone RCCA reconstruction. Doppler flow studies at 4 to 7 months of follow-up in five patients demonstrated slightly higher right-sided versus left-sided peak systolic, end-diastolic, and mean flow velocities. No neurological or developmental problems could be attributed to vascular reconstruction. In conclusion, RCCA reconstruction is technically feasible, but due to the high prevalence of CTN at the arteriotomy site, excision of this segment is recommended at the time of arterial repair.

An interesting case presentation: ultrasound diagnosis of primary atrial thrombosis associated with brain infarctions.

A premature infant with nonbacterial endocardial thrombosis and embolization of the cerebral circulation is presented. The patient was born at 32 weeks with a birthweight of 1480 g. Pregnancy was complicated by toxemia and placental infarctions. Echocardiographic examination by 12 hours after birth revealed a large mass in the right atrium compatible with endocardial thrombus. Follow-up echocardiograms showed a small mass in the left atrium and a decrease of the right atrial mass by day 7. Echoencephologram studies were normal on day 1. An echodense area in the subcortical white matter was seen by day 2. Other echodensities were detected by day 10. Computerized tomography studies showed areas of decreased attenuation in both hemispheres. Lung perfusion scan and renal-liver ultrasound studies were normal. All these cerebral and cardiac lesions were asymptomatic. Real-time ultrasonography is useful to diagnose asymptomatic endocardial thrombosis and its cerebral complications in premature infants.