Gene therapy for cardiovascular disorders: is there a future?

Incidence of cardiovascular disease has reached epidemic proportions in spite of recent advances in improving the efficacy of pharmacotherapeutics. This has led many to conclude that drug therapy has reached a plateau in its effectiveness. As a result, our efforts have been diverted to explore the use of gene transfer approaches for long-term control of these pathophysiological conditions. The purpose of this review is to present various approaches that are being undertaken to provide "proof of principle" for gene therapy for cardiovascular diseases. Finally, we will discuss the future of gene therapy and other new technologies that may further advance this field of therapeutics.

The evaluation of percutaneous central venous catheters--a convenient technique in pediatric patients.

OBJECTIVE: To evaluate the feasibility and effectiveness of 3 different types of silastic catheters that were used for percutaneous central venous catheterization (PCVC) through peripheral veins. DESIGN AND SETTING: The study was prospective and consecutive for 6 years at a pediatric/neonatal intensive care unit and pediatric ward in Veterans General Hospital-Taipei, a university-affiliated medical center, in Taiwan, ROC. PARTICIPANTS AND INTERVENTIONS: The patients who had PCVC were consecutively enrolled from January 1988 to December 1993. Three types of silastic catheters were used. The classification was according to the caliber as small catheter (SC, 0.30 mm ID), mid-size catheter (MC, 0.51 mm ID) and large catheter (LC, 0.64 mm ID). The same insertion technique, catheter-through-needle, was used for all PCVC placements through the peripheral vein. After insertion, each catheter was connected to a conventional short cannula (24-, 22-, or 20-gauge) of compatible caliber, and then linked to the infusion system. RESULTS: 1318 PCVCs were used in 1126 consecutive patients, that included 754 SCs in 649 infants (among them 60.9% were less than 1500 g), 383 MCs in 319 toddlers, and 181 LCs in 158 children. Mean (SD) body weight at the time of catheter insertion was SC 1.7(0.9)kg, MC 12.1(6.5)kg and LC 19.3(7.6)kg. Overall, mean (SD) duration of these PCVC was 16.4(8.4) days. A significantly longer duration was noted in: (a) SC group with 19.7(10.4) days than the other two groups [MC 12.4(6.5) days, LC 11.2(5.0) days]; (b) patients with body weight equal to or less than 3.0 kg [18.7(8.6) versus 14.1(6.1); and (c) insertion sites other than external jugular vein (EJV) [18.8(9.7) versus 11.7(6.0)]. These PCVCs provided reliable venous access for multiple purposes such as hyperalimentation, venous access or sampling of blood, antibiotic therapy and chemotherapy. MC and LC were also used for monitoring the central venous pressure. Most of the time, SC and MC were inserted through the superficial peripheral vein of the scalp, neck and extremities, while LC was almost approached via the EJV. The overall success rate of insertion was 92.4% (1318/1427). No significant difference was observed among the different catheter groups [93.4% (754/807) in SC, 90.5% (383/423) in MC and 91.9% (181/197) in LC] and the different insertion sites. Within each group of PCVC, more than eighty percent of catheters were removed electively: 83.3% in SC, 89.6% in MC and 84.5% in LC. Probable catheter-related sepsis accounted for 2.7% (36/1, 318) of all PCVCs. With this study, the cost of each PCVC set is 3.0 US dollar. CONCLUSION: This study indicates that the use of three different calibers of silastic catheter is feasible and effective for PCVC in pediatric practice.

Role of ventilation strategy on perfluorochemical evaporation from the lungs.

To study the effect of ventilation strategy on perfluorochemical (PFC) elimination profile (evaporative loss profile; E(L)), 6 ml/kg of perflubron were instilled into anesthetized normal rabbits. The strategy was to maintain minute ventilation (VE, in ml/min) in three groups: VE(L) (low-range VE, 208 +/- 2), VE(M) (midrange VE, 250 +/- 9), and VE(H) (high-range VE, 293 +/- 1) over 4 h. In three other groups, respiratory rate (RR, breaths/min) was controlled at 20, 30, or 50 with a constant VE and adjusted tidal volume. PFC content in the expired gas was measured, and E(L) was calculated. There was a significant VE- and time-dependent effect on E(L.) Initially, percent PFC saturation and loss rate decreased in the VE(H) > VE(M) > VE(L) groups, but by 3 h the lower percent PFC saturation resulted in a loss rate such that VE(H) < VE(M) < VE(L) at 4 h. For the groups at constant VE, there was a significant time effect on E(L) but no RR effect. In conclusion, E(L) profile is dependent on VE with little effect of the RR-tidal volume combination. Thus measurement of E(L) and VE should be considered for the replacement dosing schemes during partial liquid ventilation.

Cold perfluorochemical-induced hypothermia protects lung integrity in normal rabbits.

To test the hypothesis that intrapulmonary perfluorochemical (PFC) liquid may induce hypothermia, and to compare the effects of internal (IC), external (EC), and combined cooling techniques (EC + IC), 14 juvenile rabbits were randomized to EC by a cold blanket (4 degrees C, n = 5), IC by intrapulmonary cold PFC liquid lavage (4 degrees C, n = 5), or combined IC with PFC and EC (n = 4). Arterial blood gas, blood pressure, and lung mechanics were monitored, and lung histology was examined by light microscopy. The results showed that cooling rates and the time needed to be cooled down to 30 degrees C were significantly faster in EC and EC + IC than IC (p < 0.05). Blood gas analysis and cardiopulmonary function were within the normal range in all groups. Histological assessment revealed varied atelectasis in all lung regions in EC, whereas PFC-filled lungs (IC and EC + IC) demonstrated more homogenous expansion and no evidence of atelectasis. The results indicate that intrapulmonary PFC may be an effective technique to induce and/or augment hypothermia while supporting gas exchange, lung volume and pulmonary architecture.

Respiratory syncytial virus bronchiolitis.

Respiratory syncytial virus (RSV) bronchiolitis is associated with the clinical signs and symptoms of small airway obstruction. A major public health problem throughout the world, this condition is responsible for significant morbidity and mortality. Management is primarily preventive, through strict hand washing, avoidance of exposure during the respiratory illness season and intravenously administered prophylactic anti-RSV Immune globulin, especially in selected small infants with underlying cardiopulmonary disease. Supportive measures, including fluid hydration, good nutrition, aerosolized bronchodilators and steroids, may be helpful. Ribavirin may be useful in severely ill children or those with underlying cardiopulmonary disease. A significant number of patients have recurrent episodes of bronchiolitis and wheezing, and may develop asthma later in life. Avoidance of exposure to tobacco smoke, cold air and air pollutants is also beneficial to long-term recovery from RSV bronchiolitis. A number of vaccines to prevent this infection are currently being studied.

The application of a modified mini-flexible-fiberoptic endoscopy in pediatric practice.

BACKGROUND: The application of bronchoscopy in infants and small children is still restricted in most institutions because of their limited airways. The purpose of this study was to evaluate the usefulness of a modified mini (2.1 mm OD) flexible fiberoptic endoscope (FFE) in diagnosis and therapy of suspected pediatric airway problems. METHODS: A prospective two-year study was carried out in a tertiary care neonatal/pediatric intensive care unit and general ward in a children medical center of a university-affiliated hospital. The employed mini-FFE (Machida ENT-30 F III, Tokyo, Japan) was modified with the addition of an external silastic catheter (0.5 mm inward diameter, 0.9 mm outward diameter) for suctioning, oxygen delivery, and medications during study. RESULTS: Totally, 247 laryngoscopies and 212 bronchoscopies were performed in 207 patients without significant morbidity or any associated mortality. The age of patients ranged from 1 day to 10 years. About one-fifth of the procedures (larngoscopy 21.5%, 53/247; bronchoscopy 19.8%, 42/212) were performed in patients under the age of one month. Patient's body weight ranged from 650 g to 40 kg. About fifty-five percent of the procedures (laryngoscopy 55.1% 136/247; bronchoscopy 55.2%, 117/212) were performed in patients weighing less than 5 kg. The most common path of either laryngoscopy (94.3%, 233/247) or bronchoscopy (94.8%, 201/212) was through the nasal route. In 102 patients who had been demonstrated to have upper airway problems, 16 patients (15.7%) also proved to ahve significant lesion(s) below the glottis. CONCLUSIONS: This modified FFE is a safe and a valuable instrument that can serve as an important aid in the diagnosis and therapy as well as a guide for surgical intervention of respiratory tract disorders in small infants and children.

Non-traumatic injuries in childhood: an epidemiological survey.

BACKGROUND: Accident is the major cause of morbidity and mortality in childhood. The incidence of various non-traumatic injuries has increased due to proliferation of many chemical products and curiosity of little children, which needs our special attention for prevention. METHODS: Two hundred and sixty-six children were sent to the pediatric emergency room of Veterans General Hospital-Taipei from January 1990 to December 1993 with a diagnosis of non-traumatic injuries. Retrospective analysis of their medical records was performed. RESULTS: Household materials were the most common ingested material causing non-traumatic injuries, followed by drugs, foreign bodies and gases. The male to female ratio was 1.3:1. The children were most commonly 1 to 3 years of age (66.2%), especially between 13 to 24 months. Benzodiazepines, pesticides and coins were the most common causes in drug, household material and foreign body groups, respectively. Sixty-two percent of cases had symptoms, and the major presentations occurred in central nervous system. Ninety-two percent of non-traumatic injuries happened at home, and ninety-two percent of the events were accidental. Approximately thirty percent of patients needed hospitalization. Ultimately, two cases died and another three had severe sequelae. CONCLUSIONS: Boys at 1-3 years of age had the highest proportion among young victims of non-traumatic injuries especially via accidental ingestion or poisoning, and home was the most common site of event. Proper prevention with education to the parents and children is of the most importance to eliminate such injuries.

Superior vena cava syndrome in children with malignancy: analysis of seven cases.

Superior vena cava syndrome (SVCS) is rare in children. In Veterans General Hospital-Taipei, a total of 364 cases of SVC syndrome were diagnosed in the past 12 years. Of them only seven cases were younger than 18 years of age, ranging from 6 to 17 years, and they were all caused by mediastinal tumor. The underlying malignancy included malignant lymphoma in 4, teratocarcinoma in one and unknown in 2. The most common initial symptom was cough, followed in order of frequency by chest discomfort or neck mass. Dyspnea, orthopnea, swelling of head and neck, and venous engorgement might develop gradually within one to three weeks. Of the reported seven cases, two cases received immediate resuscitation upon arrival but expired in 1-2 hours. The other five cases received treatment with intravenous steroid as well as chemotherapy, and three cases also received committent emergent radiotherapy. Two of them expired 4 months and 2 years after treatment, respectively. Of the two surviving cases, one has received a complete course of chemotherapy and the other is still under regular chemotherapy in our hospital. Both of them are stable till now.

Direct tracheobronchial suction for massive post-extubation atelectasis in premature infants.

UNLABELLED: A prospective four-year study was done in a neonatal intensive care unit (NICU) to evaluate a technique, called direct tracheobronchial suction (DTBS), for rapidly removal of obstructive secretions from the tracheobronchial tree in newborn infants with massive post-extubation atelectasis (PEA). Selected cases who met the following criteria were enrolled: 1) developing new massive atelectasis within 48 hours after extubation; 2) no response to vigorous chest physiotherapy(CPT) and continuous deterioration; and 3) no air-bronchogram in the atelectatic lung field. DTBS was carried on at bedside by direct insertion a 6.5 Fr suction catheter into tracheobronchial tree and suctioning. Clinical and laboratory assessments were made in each case prior to and at two hours after DTBS for comparison. A total of 145 (19.7%, 145/736)) PEA occurred in a consecutive 736 postextubated newborn infants. Thirty-one atelectasis (4.2%, 31/736) that developed in 18 infants were managed with DTBS. There was a significant higher incidence of PEA developed, as well as a higher ratio of PEA been treated by DTBS, in the group of body weight < 1,500 g than the group of > or = 1,500 g. All except one infants weighed less than 1,500 g, with a mean of 1,043 +/- 269 g. Sixteen infants had been intubated for more than seven days with a mean of 14.1 +/- 5.0 days. Nine infants required more than one session of DTBS. DTBS was quite effective in immediate removal of retained secretions and improvement of pulmonary condition. By clinical assessment, respiratory distress improved with increased audible air entry on the affected lung, decreased chest retractions, and a significant fall in respiratory rate and heart rate. Arterial blood gases analysis showed significant improvement of pH, partial pressure of carbon dioxide and oxygenation ratio. By chest radiograph, DTBS resulted partial or nearly complete resolution of the atelectasis in all cases. DTBS procedures were well tolerated by all infants without significant sequelae. CONCLUSION: This study suggests that DTBS is a simple and effective therapeutic modality to rapidly correct the massive PEA which resist to vigorous CPT in small infants.

Complications of intra-cardial placement of silastic central venous catheter in pediatric patients.

UNLABELLED: A three-year prospective study was undertaken to determine the incidence and early complications from intra-cardiac placement of percutaneous central venous catheter (CVC). CVC was inserted by using "Catheter-through-needle" technique, and the insertion length was measured by body surface landmark. CVC course and tip location were routinely checked by roentgenography. Echocardiography was performed in case of arrhythmia. After analysis of 784 CVCs, 104 (13.3%) were proved to be intra-cardial, as located by either roentgenography or echocardiography. However, catheters passed via the upper trunk (14.5%) were significantly (p < 0.05) more intra-cardially located than those via the lower trunk (4.8%). Catheters which passed via the right upper trunk veins (basilic, cephalic, or external jugular veins) were also more intra-cardially located than those via their left veins counterparts, but the finding was not statistically significant (p > 0.05). The mean body weight (3.1 +/- 2.4 kg) in the intra-cardial placement group was significantly (p < 0.05) less than that in the non-intracardial placement group (7.9 +/- 4.5 kg). In intra-cardial placement patients, 32 cases (30.8%) had episode(s) of cardiac arrhythmia including 31 premature ventricular depolarization and 1 supra-ventricular tachycardia. All cases showed the presence of intra-ventricular catheter. All arrhythmias ceased abruptly after the catheters were pulled from the hearts. No other early complications were observed. CONCLUSIONS: the incidence of the intracardiac placement of CVC is high, especially in small infants or when the insertion via the upper trunk. Short term intra-cardiac catheter placement has a benign clinical course except that the intraventricular catheter may cause arrhythmia. However, this kind of arrhythmia can be resolved spontaneously by withdrawing the catheter.

The efficacy of different umbilical cord care regimens: an in vitro study on their drying and antimicrobial effect.

BACKGROUND: Topical regimens have been used for umbilical cord care for different purposes, but their drying efficacy has rarely been statistically analyzed. We designed an in vitro study with six regimens to determine which one can achieve the best drying and antimicrobial effects in umbilical cord care. METHODS: Twenty-seven umbilical cords were resected when babies were born. Each cord was cut into seven segments in appropriate length and randomly labeled to seven groups. Six regimens including 75% alcohol, 90% alcohol, tincture povidone-iodine, aqua povidone-iodine, Chinese herbs, and one powder agent (M) were used topically on six groups of umbilical cords once daily. The control group received no treatment. Daily weight of the cords was recorded for 7 days, and bacterial culture was performed on the sixth day. RESULTS: All study groups presented similar algebraic functional relationship between weight change and time. The drying effect occurred mostly within the first 3 days (weight loss 88.6%), especially on the first day (62.1%). Mean ratio of the final weight/initial weight was 10.2%. Significant day-by-day weight loss was noted from day 1 to day 5 (p < 0.001). Both aqua and tincture povidone-iodine groups showed not only satisfied drying effect but also significantly better antimicrobial effect than other groups. CONCLUSIONS: Povidone-iodine has both good drying and antimicrobial effects in umbilical cord care. As the topical use of povidone-iodine has been reported to relate to transient neonatal hypothyroidism, we suggest it to be used only as a good substitute if there are signs of umbilical cord infection.

Intraspinal enterogenous cyst: report of one case.

A 13-year-old boy with an intradural extramedullary enterogenous cyst is presented. He presented with progressive weakness of lower limbs. The myelography and computed tomography scan of spinal cord demonstrated an intradural, extramedullary lesion at the spinal level of T 7-9. A cystic lesion was discovered during operation. The cyst caused the spinal cord compression and was related to neurological deficit. Histologically, it was confirmed by Periodic Acid-Schiff and Alcian Blue stain to contain mucin. He recovered very well after surgical removal of the cyst.

The relationship between serum and saliva erythropoietin concentrations in adults, full-term and premature infants.

Simultaneous blood and saliva samples were collected for determination of the relationship between serum and saliva erythropoietin (EPO) concentrations in 12 adults (Group I), 15 full-term neonates (Group II), and 11 premature infants (Group III). Saliva was collected with a modified sputum-collecting tube combined with a vacuum suction pump. Serum and saliva EPO concentration was measured by enzyme-linked immunosorbent assay. The relationship between serum and saliva concentrations was explored using (1) regression analysis and (2) serum-to-saliva ratio. Salivary concentrations approximated 15 to 30% of the serum concentrations based on the serum-to-saliva ratios. Significant correlation was observed between serum and salivary concentrations in each group (p < 0.05). The regression analyses produced formulas for predicting serum EPO concentrations from saliva EPO concentrations which seemed to fit the data well. The resulting formula is surprisingly consistent with that derived from Group I. The ratio models seem to fit the data well as regression models. From the results it is concluded that the use of salivary samplings for serum EPO in adults, full term and premature infants may be a possible alternative method to blood samplings.

Experiences with high-frequency oscillatory ventilation in premature infants with respiratory distress syndrome.

BACKGROUND: High-frequency oscillatory ventilation (HFOV) has been used in treating premature infants with respiratory distress syndrome who have a low incidence of ventilation-associated lung injury. Herein, we report our initial clinical experience in using HFOV to treat such infants. METHODS: From October 1996 to February 1997, 10 premature infants with severe respiratory distress syndrome treated with HFOV were retrospectively evaluated. Clinical course and laboratory data collected during treatment were analyzed. Parameters evaluated included patient survival rate, incidence of chronic lung disease and morbidity associated with HFOV usage. RESULTS: The mean gestational age was 29 +/- 2 weeks; mean birth weight, 1,182 +/- 342 g; and mean period of HFOV treatment, 3.4 +/- 1.9 days. One patient died of sepsis due to infective pancarditis. Two patients developed moderate chronic lung disease at 30 days post delivery and in one of these patients, the disease persisted at 36 weeks' of age. The overall survival rate was 90%. No patient developed air-leak syndrome during the course of treatment. CONCLUSIONS: Our initial experience demonstrated that using HFOV in treating premature infants with severe respiratory distress syndrome was safe and effective. The incidence of moderate to severe chronic lung disease or air-leak syndrome following HFOV was low.

Pancarditis in an extreme premature newborn following central venous catheterisation: report of one case.

We report a rare complication of pancarditis in an extreme premature neonate with a peripheral inserted central venous catheter which was positioned in the right atrium. She showed a picture of sepsis, pulmonary embolism, and heart failure. This case emphasizes the need for careful monitoring of the neonate with a central venous catheter to eliminate possible sequel. Echocardiography may help in making an early diagnosis of endocarditis in neonates.

High-frequency oscillatory ventilation--a new management for respiratory distress syndrome and intractable respiratory failure.

High-frequency oscillatory ventilation (HFOV) has been proved to decrease the incidence of volutrauma and improve oxygenation and ventilation in severe pulmonary diseases by many investigators with animal studies and clinical reports, particularly in prematurities with severe respiratory distress syndrome. Patients with intractable respiratory failure or air-leak syndrome may be rescued by HFOV. During HFOV small volume, less than dead space, is delivered at high frequencies. Both inspiration and expiration are active. Oxygenation is mainly maintained by mean airway pressure to achieve optimal lung volume. Carbon dioxide elimination is mainly controlled by delivered volume. Mean airway pressure, fraction of inspiratory oxygen and amplitude are the only three items that need frequent adjustments after initial settings. The first two items determine the oxygenation and the last one determines ventilation. Careful monitoring of conditions the patients, discontinuous learning and cooperation of all coworkers are important to use the new therapy. Further studies with long-term follow-up are important to assess its appropriate role in different treatment methods and different degrees of respiratory diseases.

Preirradiation chemotherapy for very young children with brain tumors.

Standard management of malignant brain tumors includes either surgical resection alone or surgery followed by irradiation. However, neuroaxis irradiation administered to very young children for primary intracranial tumors is often associated with major late side effects. To delay irradiation and evaluate the efficacy of preirradiation chemotherapy, we treated 9 young children (aged less than 3 years), who had newly diagnosed brain tumors and underwent total or subtotal resection, with a combination of chemotherapy including vinblastine, cisplatin, and etoposide every 3-4 weeks for 6-14 courses between 1988 and 1992. There were malignant gliomas in four patients, medulloblastomas in three, and ependymomas in two. A response to preirradiation chemotherapy (complete remission or partial remission) occurred in seven out of nine cases. Only one patient had progressive disease during the chemotherapy period. Preirradiation chemotherapy with vinblastine, cisplatin, and etoposide might be a highly effective combination allowing delay of radiation therapy in very young children with brain tumors. Acute and subacute toxicity of chemotherapy in this study was mild.

The effect of povidone-iodine on thyroid function of neonates with different birth sizes.

The aim of this study was to elucidate the role of povidone-iodine (PV-I) on thyroid function of newborns with different birth sizes in a high iodine-intake city. Serial measurements of serum thyroxine (T4) and thyrotropin (TSH) levels were done in 44 newborns locally treated with 10% PV-I for insertion of percutaneous central venous catheters. The results showed that the thyroid function was influenced prominently in very-low-birth weight (VLBW) babies. TSH went significantly higher after application of PV-I for 48 hours in VLBW babies. The smaller the babies were, the lower the T4 at birth and thereafter. In conclusion, PV-I is suggested to be avoided for single application on a wide skin surface in VLBW babies, even in an area with high iodine-intake population.