Progressive aortic root and pulmonary artery aneurysms in a neonate with Loeys-Dietz syndrome type 1B.

Loeys-Dietz Syndrome (LDS) is an autosomal dominant aortic aneurysm syndrome with multisystem involvement, caused by heterozygous mutations of transforming growth factor beta receptor type 1 (TGFBR1) or type 2 (TGFBR2) genes. We report on a neonate with the disorder caused by a known TGFBR2 mutation, who developed neonatal-onset progressive dilation of the aortic valve and aneurysms of the aortic root and main pulmonary artery (PA) associated with a large left-to-right shunt via a ventricular septal defect (VSD) and an atrial septal defect. He also had skeletal features (flexion contractures of the fingers, talipes equinovarus, a cleft palate, and joint laxity), mild facial dysmorphisms, and developmental delay. The dilation and aneurysms progressed after PA banding at age 12 days; and the patient received an intracardiac repair of the defects and PA plasty at age 42 days, followed by no further progression of the dilation and the aneurysms. Neonates with generalized hypotonia, a cleft palate, inguinal herniae, musculoskeletal features such as camptodactyly and talipes equinovarus, and a cardiac murmur should be suspected to have LDS, and extensive cardiovascular evaluation and testing of TGFBR1 and TGFBR2 are recommended. LDS patients with cardiac defects that lead to a large left-to-right shunt and congestive heart failure such as VSD should be considered for intracardiac repair even in early infancy.

Inflammatory cytokines regulate glycoprotein subunit beta5 of thyrostimulin through nuclear factor-kappaB.

Thyrostimulin is a heterodimeric hormone comprised of two glycoprotein hormone subunits, namely glycoprotein hormone subunit alpha2 and glycoprotein hormone subunit beta5 (GPB5). Immunological studies have revealed that both subunits colocalize in human pituitary corticotroph cells. Although recombinant thyrostimulin protein selectively activates the TSH receptor and has thyrotropic activity in rats, its biological functions have not been clarified. To explore the physiological regulators for the GPB5, the 5'-flanking region of the GPB5 coding sequence up to 3-kb upstream was analyzed by luciferase reporter assays. We found that nuclear factor-kappaB (NF-kappaB) markedly activated GPB5 transcription. Disruption of the putative NF-kappaB-binding motifs in the GPB5 5'-flanking region silenced the GPB5 activation by p65. Chromatin immunoprecipitation assays revealed that recombinant p65 bound to the predicted NF-kappaB-binding sites. Because NF-kappaB is known to associate with acute phase inflammatory cytokines, we examined whether TNFalpha or IL-1beta could regulate GPB5. Both these cytokines activated GPB5 transcription by 2- to 3-fold, and their effects were abolished by the addition of MG132, a NF-kappaB inhibitor. Our results suggest that inflammatory cytokines positively regulate thyrostimulin through NF-kappaB activation.

Novel treatment for lithium-induced nephrogenic diabetes insipidus rat model using the Sendai-virus vector carrying aquaporin 2 gene.

Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/DeltaF) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/DeltaF vector carrying a human AQP2 gene (AQP2-SeV/DeltaF) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.

Risk factors for early death in neonates with Down syndrome and transient leukaemia.

Transient leukaemia (TL) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells in the peripheral blood that resolves spontaneously. Some TL patients die at an early age due to organ failure. Seventy DS patients with TL were studied retrospectively to identify clinical and laboratory characteristics associated with early death (<6 months of age). Sixteen of 70 patients (22.9%) died early. The main causes of death were organ failure, particularly hepatic and cardiopulmonary failure. On univariate analysis, early gestational age (EGA), high white blood cell (WBC) count (> or =100 x 10(9)/l), percentage of peripheral blasts, elevated aspartate transaminase (AST), elevated direct bilirubin (DB), and low Apgar score were significantly associated with poor survival. On multivariate analysis, EGA, WBC count, and DB were independent predictors of poor outcome. A simple risk stratification system combining EGA and WBC count was devised to predict poor outcome. Term infants (EGA > or = 37 weeks) whose WBC count was lower than 100 x 10(9)/l had the best outcome [7.7% (3/39) died early], while preterm infants (EGA < 37 weeks) whose WBC count was higher than 100 x 10(9)/l had the worst outcome [54.5% (6/11) died early]. This stratification system may be useful for identifying high-risk patients who need early therapeutic interventions.

Biochemical roles of the oligosaccharide chains in thyrostimulin, a heterodimeric hormone of glycoprotein hormone subunits alpha 2 (GPA2) and beta 5 (GPB5).

Thyrostimulin is a heterodimeric hormone composed of GPA2 and GPB5, and shares the thyroid-stimulating hormone receptor (TSHR). Thyrostimulin has three N-linked oligosaccharide chains, two in GPA2 and one in GPB5. The roles of these N-linked oligosaccharides in secretion, heterodimer formation and signal transduction were analyzed. Recombinant GPA2s lacking either of the two oligosaccharides were obtained from conditioned medium, whereas dual site-disrupted GPA2 and the GPB5 mutant were not expressed in either the conditioned medium or cell lysate. The binding between GPA2 and GPB5 was weaker than that between TSH subunits GPA1 and TSH beta. Neither of the oligosaccharides in GPA2 had significant effects on heterodimerization. Disruption of either of the oligosaccharides in GPA2 significantly decreased receptor activation, suggesting their critical role in receptor activation.

The LIM domain homeobox gene isl-1 is a positive regulator of glycoprotein alpha 2 (GPA2), a subunit of thyrostimulin.

Two glycoprotein hormone subunits, glycoprotein hormone subunit alpha (GPA) 2 and glycoprotein hormone subunit beta (GPB) 5, have recently been discovered. When expressed as recombinant proteins, they heterodimerize to form a novel thyrotrophic hormone, thyrostimulin. Recently, we have shown that GPA2 is expressed in both human pancreas and anterior pituitary. To explore the transcriptional regulation of GPA2, we identified from human pancreas full length RNA, the transcription start site (TSS) of the human GPA2 gene. A potential binding site for the LIM homeodomain transcription factor isl-1, which is closely associated with endocrine organs, was found at -2368 to -2363 bp upstream from TSS. The exogenously expressed isl-1 dose-dependently increased the GPA2 promoter activity up to two-fold in the AtT20 mouse corticotroph cell line. In chromatin immunoprecipitation assays we show the binding of isl-1 molecule to the predicted site. The reporter assay also showed that GPA2 transcription is unaffected by tri-iodothyronine or thyroid hormone receptor beta1 (TRbeta1), suggesting that the regulation of GPA2 might be different from the regulations of GSUalpha or TSHbeta, known as hypothalamus-pituitary-thyroid (HPT) axis. This study illustrated that human GPA2 is positively regulated by isl-1, suggesting that this protein associates with endocrine systems including the pituitary and pancreas.

Ganciclovir therapy for congenital cytomegalovirus infection in six infants.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is common, and its morbidity rate is high. Ganciclovir (GCV) treatment has been used for congenital CMV infection, but there are few reports on viral loads associated with GCV therapy. METHODS: A real-time PCR assay was used to monitor viral load in 6 cases of symptomatic CMV infection that received GCV therapy. Initially GCV was given at a dose of 5-12 mg/kg/d for 2-7 weeks. In 2 cases, additional doses were given as symptoms returned. RESULTS: After GCV administration, active signs of chorioretinitis, thrombocytopenia and anemia disappeared or improved in all cases. During GCV therapy, viral loads decreased while patients improved clinically and increased again when GCV therapy was stopped. Although CMV DNA continued to be detectable for a long period, clinical findings did not always worsen. In 2 cases, an improvement of hearing loss was observed. CONCLUSION: GCV therapy transiently suppresses the CMV concentrations. Subsequent increases of viral titers do not appear to be correlated with the clinical course or neurologic outcome.

Effects of a school-based education program for schistosomiasis control.

The role and effect of school-based education for schistosomiasis control needs to be explored further to raise the standard of health in the widely infected areas over the world. This study investigated the effect, particularly the retention or duration of effect, of a school education program for schistosomiasis control. The study was conducted from September 2000 to February 2001 in a district of Mount Darwin, Zimbabwe. Two hundred ninety-nine fifth graders from 8 primary schools were examined for their knowledge, attitude, beliefs and practice regarding schistosomiasis, based on a KABP form, three times in succession. The examinations were a baseline examination, a pre-examination checking for the effect of the program, and a post-examination assessing retention after three-months. Analyses of the examination results indicated a considerable effect of the program in all aspects except for practice. Further detailed analyses on 161 matched pair subjects comparing the difference between the pre- and post-examination results demonstrated how the subjects maintained or rather increased what they had learned, illustrating an amplifying resonance or percussion effect, that is, a group dynamic effect in the school setting. No clear correlation, however, was shown between the education effect and the infection rate of the subject groups. Ways to prevent the deterioration of the practice aspect, and the cause of the negative correlation between the infection rate and education effect need to be closely investigated, while trying out more participatory-type education is an absolute necessity.

Combating HIV/AIDS in Mainland China: an epidemiological review of prevention and control measures.

Two decades have already passed since the first HIV/AIDS case was described in 1981. Cumulatively, over 20 million people have unfortunately lost their lives, and more than 40 million people are now living with HIV, and most of them are from developing countries. China, as the biggest developing country, has an impact on the epidemic of HIV/AIDS. From the first case of AIDS diagnosed in Mainland China in 1985, the epidemic has spread at an alarming rate. The feature of HIV/AIDS spread in Mainland China concerns its geographical characteristics that can be described as occurring in three phases. According to data from World Health Organization (WHO), it was estimated that about 840,000 people are living with HIV/AIDS in China, and 80,000 of them have already developed AIDS. WHO warned that, if there were no effective preventive measures adopted, that the number of HIV/AIDS infected cases would reach 10 million in China by 2010. In this study, we described the current situation of the epidemic of HIV/AIDS, as well as an historic review. The development of policy-making and the control measures are also highlighted. The experience from China described in this study would hopefully be for more public awareness of this crisis that is threatening all the citizenry of China.

Evaluation of cytomegalovirus infections transmitted via breast milk in preterm infants with a real-time polymerase chain reaction assay.

OBJECTIVE: Preterm infants are at greater risk of symptomatic cytomegalovirus (CMV) infection than term infants. Breast milk is the main source of perinatal CMV infections. This study evaluated the kinetics of CMV load in breast milk and the rate of postnatal CMV transmission via breast milk from mothers to their preterm infants. METHODS: This was a prospective study of 30 mothers and their 43 preterm infants. The infants either had a gestational age of <34 weeks or weighed <2000 g at birth. Breast milk, serum, and urine samples were collected every 2 weeks until discharge, and screened for CMV infection using a real-time PCR assay. Most of the breast milk had been preserved at -20 degrees C before feeding to the preterm infants. RESULTS: Twenty-four mothers (24 of 30, 80%), who had 34 preterm infants, were CMV immunoglobulin G positive. Twenty-one (87.5%) of the 24 seropositive mothers, who had 30 preterm infants, had detectable CMV deoxyribonucleic acid (DNA) in breast milk during the study period. Most breast milk became positive for CMV DNA 2 weeks after delivery. Viral DNA copy numbers increased until they peaked at 4 to 6 weeks. Afterward, the CMV DNA copy numbers decreased. Of the 30 infants who were fed CMV DNA-positive breast milk, CMV infection was confirmed in 3 infants. However, they had no clinical symptoms of CMV infection. CONCLUSIONS: Despite the high rate of CMV DNA in breast milk, symptomatic infections in the preterm infants did not occur. These results might be associated with the method of breast milk preservation and the population we studied. CMV infections transmitted via breast milk feeding did not have much impact on preterm infants in our institutes.