Cerebral blood flow velocity and pulsation in neonatal respiratory distress syndrome and periventricular hemorrhage.

The present study addressed the hypotheses that cerebral ischemia and/or excessive cerebral blood pulsation contribute to periventricular hemorrhage in preterm newborns with respiratory distress and that the pulse width is a valuable tool to estimate the contribution of cerebral blood pulsation. These hypotheses were tested by following preterm newborns at risk for respiratory distress and periventricular hemorrhage. We monitored for cerebral blood flow velocity (CBFV), cerebral pulse width, and cerebral pulsatility index; for patent ductus arteriosus, capillary Pco2, heart rate (HR) and behavior; and for the occurrence of respiratory distress and periventricular hemorrhage (PVH). The data obtained were analyzed with linear regression with the mode of respiration (spontaneous or supported) and postnatal age as additional covariates. We observed that (a) respiratory distress, either uncomplicated or complicated by PVH, correlates with a low CBFV and a high cerebral pulsatility index; (b) PVH also correlates with a high cerebral pulse width; (c) the increased pulse width precedes the onset of the hemorrhage; and (d) these CBF alterations can be partly attributed to ductal shunting and are ameliorated by mechanical ventilation.

Shortened and diminished pubertal growth in boys and girls treated for acute lymphoblastic leukaemia.

Statural growth during puberty was studied longitudinally in 28 patients treated for acute lymphoblastic leukaemia. All patients received prophylactic cranial irradiation. The age at diagnosis was below 7 years, the age at final investigation was above 16 years for girls and above 18 years for boys. Growth was analysed using the Kernel estimation. In girls the onset of puberty and menarche was at a younger age, as compared to reference values, and the duration of the pubertal growth spurt was shorter. Compared to early maturing girls, the growth velocity at peak height velocity was lower. This resulted in a final height which was shorter than expected on the basis of the height standard deviation score before the start of puberty. In boys the duration of the pubertal growth spurt was shorter and the height gain during the growth spurt less than in the reference population. In both sexes the bone age development was accelerated.

Influence of treatment modalities on body weight in acute lymphoblastic leukemia.

Weight for height of 92 patients (51 girls and 41 boys) treated for acute lymphoblastic leukemia (ALL) was evaluated in a longitudinal study. Fifty-four patients received cranial irradiation (CI) with a dose of 18 or 24 Gy and 38 patients did not receive CI. Seventy-seven patients were treated according to a normal-risk protocol and 15 patients received more intensive chemotherapy according to a high-risk protocol. In most of the patients the duration of follow-up was 12 years for irradiated patients and 4.5 years for the nonirradiated patients. Thirty of 92 patients were treated according to a protocol without CI, but with a difference in the use of corticosteroids: 19 patients received dexamethasone during the remission-induction and maintenance treatment and 11 patients received prednisone. The influence of dexamethasone vs. prednisone, sex, CI and high-dose vs. low-dose chemotherapy on weight for height was evaluated. Patients who received dexamethasone showed a significant increase in weight for height immediately after the start of therapy. In patients who received CI, weight for height significantly increased after the first year of treatment. The overweight in these patients persisted during the whole follow-up period. The weight for height of patients treated with prednisone and of patients who did not receive CI was below the mean of the normal population during treatment but was not different from normal after cessation of therapy. No difference in weight gain was seen between boys and girls and between patients who were treated with high vs. normal-risk protocols.

Catch-up growth after prolonged hypothyroidism.

UNLABELLED: This report presents an analysis of four patients who suffered from longstanding untreated hypothyroidism, with special attention to the phase of catch-up growth after the start of L-thyroxine treatment. Although a permanent height loss could not be prevented, the capacity to establish a remarkable catch-up growth spurt proved to be still intact, even after a long period of thyroid dysfunction. CONCLUSION: Catch-up growth in hypothyroidism may be incomplete if treatment has been started shortly before or during puberty.

Asymmetry of the cerebral blood flow: an ultrasound Doppler study in preterm newborns.

The purpose of this study was to investigate whether the preference of periventricular hemorrhage (PVH) for the left hemisphere is due to asymmetry of cerebral blood flow (CBF) and, if so, whether this asymmetry is due to patent ductus arteriosus (PDA). Thirty-three preterm newborns at risk for PVH were followed during their first 5 days after birth. Internal carotid CBF velocity (CBFV) and the flow direction in the common pulmonary artery, both determined by ultrasound Doppler, served as measures of CBF and PDA, respectively. The difference between right and left CBFV was analyzed statistically, with outcome, PDA, capillary PCO2, behavior, heart rate, and the average of right and left CBFV as covariates. Infants who developed PVH (n = 7) exhibited CBFV asymmetry to the disadvantage of the left side. This finding was partially attributable to PDA. Without PVH there was no significant CBFV asymmetry. Because all hemorrhages were bilateral, a relationship with the side of the hemorrhage could not be explored. In conclusion, asymmetry of CBFV is not normal, but is associated with PVH and PDA.

Chemotherapy plays a major role in the inhibition of catch-up growth during maintenance therapy for childhood acute lymphoblastic leukemia.

OBJECTIVE: In children treated for acute lymphoblastic leukemia (ALL), catch-up growth occurs after cessation of therapy and not during maintenance therapy. In this study we investigated whether this inhibition of catch-up growth during maintenance treatment is attributable to the influence of chemotherapy or to the influence of corticosteroids. PATIENTS: Forty-six children treated for ALL were included in the study. In 27 patients maintenance therapy comprised vincristine (VCR), prednisone (Pred), or dexamethasone (Dexa) alternated with 6-mercaptopurine (6-MP) and methotrexate (MTX) and 19 patients received maintenance therapy with 6-MP and MTX only. Treatment did not include cranial irradiation. RESULTS: Statural growth during maintenance treatment was comparable in both groups over the study period of 1.5 years. CONCLUSION: Chemotherapy with 6-MP and MTX, and not corticosteroids, is the main factor that prevents catch-up growth from occurring during maintenance therapy for ALL.

Influence of treatment modalities on prepubertal growth in children with acute lymphoblastic leukemia.

The statural growth of 85 prepubertal children treated for acute lymphoblastic leukemia was evaluated in a longitudinal study over 4.5 years. Patients were divided into three groups according to central nervous system prophylaxis: 37 patients received cranial irradiation with a dose of 24 Gy, 15 received a dose of 18 Gy, and 33 were not irradiated. According to the risk of leukemia, patients were divided into normal-risk (n = 74) and high-risk (n = 11) groups. The duration of treatment was 2 years, during which all patients showed growth retardation. The relative standard deviation score for height declined from 0 to -0.7 for the irradiated patients and from 0 to -0.2 for the non-irradiated group (P = 0.0001). There was no difference in growth pattern between cranial irradiation with 18 versus 24 Gy and chemotherapeutic treatment according to high-risk versus normal-risk protocols. However, a negative synergistic effect of more intensive chemotherapy and cranial irradiation on growth was demonstrated.

The influence of artificial ventilation on heart rate variability in very preterm infants.

To study the influence of artificial ventilation rate on neonatal heart rate variability (HRV), ECG and respiratory impedance curves were recorded four times a day in 20 preterm infants (< 33 wk) during the first 3 d after birth while the infants were ventilated at a wide range of ventilator rates. The contents of selected frequency bands within the R-R interval power spectrum were calculated for 3-min periods. Respiratory distress syndrome severity was assessed at each measurement. Respiratory sinus arrhythmia (RSA) induced by the ventilator appeared to mimic spontaneous RSA. As in spontaneous respiration, the amount of RSA (power in a frequency band around the respiratory rate) increases as the ventilation rate decreases. This phenomenon is most probably due to entrainment with baroreflex-related fluctuations in the heart rate. Although the artificial ventilation rate influences RSA and thus high-frequency HRV, an increase in respiratory distress syndrome severity results in a decrease in low-frequency HRV. Thus, the attenuation of low-frequency HRV by respiratory distress syndrome is not likely to be due to artificial ventilation.

Influence of end expiratory pressure on cerebral blood flow in preterm infants.

The effect of interruption of positive and expiratory pressure (PEEP) on cerebral blood flow velocity (CBFV) and CBF fluctuation (CBFF) in the internal carotid arteries and on heart rate, restlessness and wakefulness has been studied in 17 mechanically ventilated neonates with RDS. A decrease in CBFV was found, but no significant change in CBFF. Multiple regression analysis showed that the decrease in CBFV is less pronounced if the PEEP interruption is accompanied by restlessness. It further appeared that the decrease in CBFV is more pronounced if CBFV is high, the ductus arteriosus is patent, or RDS follows a complicated course. These findings indicate that PEEP supports CBF, probably by a decrease in ductal stealing from the brain. Therewith PEEP protects against cerebral hypoperfusion which is one of the major risks in RDS and immaturity. Furthermore, our findings suggest that the decrease in CBF during PEEP interruption is moderated by restlessness and accentuated by brain damage.

Cerebral blood flow fluctuation in neonatal respiratory distress and periventricular haemorrhage.

The relationship of cerebral blood flow fluctuation (CBFF) with periventricular haemorrhage (PVH) and respiratory distress syndrome (RDS) was studied in 35 preterm newborns. CBFF was defined as the interquartile range in the ensemble of pulses of a 20-s Doppler recording of CBF velocity (CBFV) in the internal carotid artery. We found a statistically significant increase in end diastolic CBFF in PVH and RDS. This increase was related to the mode of respiration (spontaneous or mechanically supported), the state of the ductus arteriosus, and the level of end diastolic CBFV. Differences before and after the onset of PVH were not found. In view of this, we conclude that RDS increases CBFF, that this increase is related to pleural pressure fluctuations, that these can be damped by mechanical ventilation, and that their propagation to the CBF is promoted by patency of the ductus arteriosus and foramen ovale. Whether the CBFF increase causes PVH, or is merely an expression of coincident RDS, remains a question that needs further investigation.

Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty.

Familial male-limited precocious puberty is a male-limited autosomal dominant condition. It is characterized by increased testosterone synthesis in the absence of testicular stimulation by luteinizing hormone (LH). We hypothesised that an abnormal configuration of the LH receptor might autonomously activate G protein coupling, and thereby cause the overproduction of testosterone in this condition. To test this hypothesis, we screened for mutations in a part of the LH receptor gene that is important for G protein binding. DNA sequence variation was detected in 2 out of 5 families with male-limited precocious puberty by the single strand conformation polymorphism technique. Direct sequencing demonstrated different single nucleotide substitutions in the sixth transmembrane region of the LH receptor gene. The mutations cosegregated with the disorder in both families (lod score 5.76 without recombination). Both mutations cause an amino acid substitution in the sixth transmembrane domain, close to the C-terminal portion of the third cytoplasmatic loop, a region which is important for the binding of G proteins. We conclude that familial male-limited precocious puberty cosegregates with missense mutations in the LH receptor gene. These findings support the hypothesis that increased activity of the LH receptor is the pathogenetic mechanism that causes the abnormal pubertal development in this condition.

Antibody deficiency and isolated growth hormone deficiency in a girl with Mulibrey nanism.

A combination of humoral immunodeficiency and isolated growth hormone deficiency was observed in a girl with Mulibrey nanism. The humoral immunodeficiency consisted of subnormal concentration of serum IgG, in particular IgG2 and IgG4, and low concentration of serum IgM. Serum IgA and IgD were elevated, IgE was absent. Antibody response in vivo was very low or absent and opsonization in vitro was defective. Total B-cell number was low. In addition, the serum kappa/lambda light chain ratios within the immunoglobulin classes G, A, and M were abnormal. The defective antibody response may be linked to the abnormal kappa/lambda light chain ratios. Endocrine functions were normal except for isolated growth hormone deficiency. Therapy with human growth hormone resulted in increased growth velocity but did not improve humoral immune functions.

Heart rate variability.

PURPOSE: To present an overview of the applicability of heart rate variability measurements in medicine. DATA SOURCES: During a 4-year period all new papers concerning heart rate variability were collected. A selection of the most recent publications in the presented research area was used for this review. DATA SYNTHESIS: The amount of short- and long-term variability in heart rate reflects the vagal and sympathetic function of the autonomic nervous system, respectively. Therefore heart rate variability can be used as a monitoring tool in clinical conditions with altered autonomic nervous system function. In postinfarction and diabetic patients, low heart rate variability is associated with an increased risk for sudden cardiac death. A sympathovagal imbalance is also detectable with heart rate variability analysis in coronary artery disease and essential hypertension. Besides diabetic neuropathy, in many other neurologic disorders, such as brain damage, the Guillain-Barré syndrome, and uremic neuropathy, heart rate variability analysis can provide insight into which division of the autonomic nervous system is most affected. Heart rate variability can be influenced by various groups of drugs, but it can also shed light on the mode of action of drugs. The protective effect of cardiovascular drugs in postinfarction patients has been investigated. CONCLUSIONS: Heart rate variability analysis is easily applicable in adult medicine, but physiologic influences such as age must be considered. The most important application is the surveillance of postinfarction and diabetic patients to prevent sudden cardiac death. With heart rate variability analysis, individual therapy adjustments to achieve the most favorable sympathetic-parasympathetic balance might be possible in the future.

Immunological studies in the hyper-immunoglobulin D syndrome.

Five patients with hyper-immunoglobulin D syndrome (hyper-IgD syndrome) were followed up for 3 to 8 years. In all patients studied, serum IgG3 was high. IgM decreased during the follow-up in all patients. In four of the patients serum IgA was elevated. In four patients the serum IgD kappa/lambda ratio was measured and was found to be raised in all. However, the serum total light-chain ratio and IgG, IgA, and IgM kappa/lambda ratios separately were virtually normal. In two of the patients, clinical symptoms preceded the increase in serum IgD. All patients had a history of severe reactions on immunizations in early childhood. We conclude that in hyper-IgD syndrome, other immunoglobulins may also be affected, in particular, IgA, IgM, and IgG3. The IgD light-chain ratio is also disturbed. We emphasize that clinical symptoms may herald immunological changes. This may be the result of an underlying factor causing both the clinical symptoms and, later, the increasing serum IgD levels.

Immunoglobulin G, A, and M light chain ratios in some humoral immunological disorders.

The total kappa/lambda immunoglobulin light chain ratio and the kappa/lambda ratios within each of the serum immunoglobulin classes G, A, and M were measured in thirteen patients with humoral immunological disorders. Of those patients, eight had common variable immunodeficiency whereas five patients had other forms of humoral immunological deficiencies. Eleven patients had abnormal antibody response in vivo. All but three of the thirteen patients had clearly abnormal light chain ratios in one or more of the immunoglobulin classes. We conclude that humoral immunological disorders, usually characterized by abnormal heavy chain production and a disturbed antibody response, may frequently have a concomitant abnormal synthesis of the light chains resulting in an abnormal kappa/lambda light chain ratio.

Immunoglobulin G, A and M light chain ratio in children.

Values for the kappa/lambda light chain ratio in immunoglobulins G, A and M and the total kappa/lambda ratio, measured by enzyme linked immunosorbent assay, were evaluated in serum samples from different age groups (114 children, aged from 1 month to 15 years, and 20 adults). The IgG kappa/lambda ratio decreased in the first 6 months and subsequently increased slowly during childhood towards the adult value of 2.0. The IgM kappa/lambda ratio increased at a greater rate than IgG kappa/lambda ratio in the first years of life and thereafter rose slightly throughout childhood to reach an adult value of 1.7. A decreasing IgA kappa/lambda ratio was found from 1 month of age onwards to an adult value of 1.1. The pattern of total kappa/lambda ratio was similar to the IgG kappa/lambda ratio with an adult value of 2.0.

Influences on heart rate variability in spontaneously breathing preterm infants.

To investigate the influence of maturational and physiological factors on heart rate variability in spontaneously breathing very preterm infants (n = 29) a multiparametric study was performed during the first 3 days of life in infants born at a gestational age below 33 weeks. Four times a day, RR-intervals, respiration curve and rate, transcutaneously measured blood gases and observed body movements were recorded while the infants were asleep. All data were stored simultaneously in a micro-computer. Non-invasively measured blood pressure and patency of the ductus arteriosus were documented as well. Four sets of short- (STV) and long term variability (LTV) indices were calculated. Both STV and LTV appeared to be significantly influenced by conceptional and postnatal age in the appropriate for gestational age infants. LTV was influenced by the behavioural state and body movements. During state coincidence 2 ('active sleep') LTV was influenced by respiratory rate and the variations in transcutaneous PO2. An effect of blood pressure or ductus patency could not be demonstrated.

The influence of respiratory distress syndrome on heart rate variability in very preterm infants.

In a multi-parametric study the influence of pathological neonatal conditions on heart rate variability was investigated in 60 preterm infants born at a gestational age below 33 weeks. Measurements were performed during the first 3 days of life. Four times a day, RR-intervals, respiration curve and rate, transcutaneously measured blood gases and observed body movements were recorded while the infants were asleep. All data were stored simultaneously in a micro-computer. Severity of respiratory distress syndrome (RDS), patency of ductus arteriosus and periventricular haemorrhage were documented as well. Four sets of short- (STV) and long-term variability (LTV) indices were calculated. Severe RDS was associated with a significant decrease in LTV. The influence of RDS on LTV persisted after correction for conceptional age, postnatal age, behavioural state and variations in respiratory rate and in transcutaneous PO2. Infants with a symptomatic patent ductus arteriosus had lower LTV than controls with the same severity of RDS. STV was predominantly influenced by postnatal and conceptional age, and tended to be lower in infants with periventricular haemorrhage.