Pediatric use of intravenous amiodarone: efficacy and safety in critically ill patients from a multicenter protocol

OBJECTIVE: The purpose of this study was to analyze the efficacy and safety of intravenous amiodarone in young patients with critical, drug-resistant arrhythmias. BACKGROUND: Intravenous amiodarone has been investigated in adults since the early 1980s. Experience with the drug in young patients is limited. A larger pediatric study group was necessary to provide responsible guidelines for the drug's use before its market release. METHODS: Eight centers obtained institutional approval of a standardized protocol. Other centers were approved on a compassionate use basis after contacting the primary investigator (J.C.P). RESULTS: Forty patients were enrolled. Standard management in all failed. Many patients had early postoperative tachyarrhythmias (25 of 40), with early successful treatment in 21 (84%) of 25. Twelve patients had ventricular tachyarrhythmias: seven had successful therapy, and six died, none related to the drug. Eleven patients had atrial tachyarrhythmias: 10 of 11 had immediate success, but 3 later died. Fourteen patients had junctional ectopic tachycardia, which was treated with success (sinus rhythm or slowing, allowing pacing) in 13 of 14, with no deaths. Three other patients had supraventricular tachycardias, with success in two and no deaths. The average loading dose was 6.3 mg/kg body weight, and 50% of patients required a continuous infusion. Four patients had mild hypotension during the amiodarone bolus. One postoperative patient experienced bradycardia requiring temporary pacing. There were no proarrhythmic effects. Deaths (9 [23%] of 40) were not attributed to amiodarone. CONCLUSIONS: Intravenous amiodarone is safe and effective in most young patients with critical tachyarrhythmia. Intravenous amiodarone can be lifesaving, particularly for postoperative junctional ectopic tachycardia, when standard therapy is ineffective.     

Nucleotide sequence of the coat protein coding region of the potyvirus tobacco vein-banding mosaic virus

The sequence of the 3' 1184 nucleotides of tobacco vein-banding mosaic virus (TVBMV) genome has been determined. It contains a single open reading frame which encompasses the whole of the coat protein of TVBMV. The sequence of the first 20 amino acids at the N-terminal region of the coat protein has also been determined chemically to be GDDQTVDAGKNVQSNQKQRN. The sequence matches the translation product of the open reading frame starting with amino acid-271; a glycine residue. Thus the coat protein of TVBMV has a calculated M(r) of 30,210. The 3' non-coding region of TVBMV is 185 nucleotides in length. Sequence alignment of the coat proteins or the 3' non-coding regions from TVBMV and other reported potyviruses indicated that TVBMV is a separate species of the potyvirus genus.     

Pretreatment with a competitive NMDA antagonist D-CPPene attenuates focal cerebral infarction and brain swelling in awake rats

The purpose of the study was to assess effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPPene) upon focal cerebral infarction and brain oedema in the rat. Focal cerebral ischaemia was produced by permanent occlusion of the middle cerebral artery under halothane anaesthesia. The anaesthetic gas was discontinued immediately after the occlusion and the rats were killed 24 hours later. Cerebral infarction and brain swelling were each assessed on the frozen brain sections at 8 predetermined coronal planes. Pretreatment with D-CPPene (4.5 mg/kg i.v. followed by continuous infusion at 3 mg/kg/h until sacrifice) 15 minutes prior to MCA occlusion, significantly reduced the volume of infarction in the cerebral hemisphere by 29% (p < 0.05). Brain swelling, obtained by subtracting the nonischaemic hemispheric volume from the ischaemic hemispheric volume, was significantly reduced with D-CPPene treatment and the mean reduction in swelling (34% less than the controls: p < 0.001) proportionately similar to the decrease in infarct volume in the same animals. These data indicate that systemic administration of the competitive NMDA receptor antagonist D-CPPene has neuroprotective effects against ischaemic brain damage, and the reduction in brain swelling occurs in parallel with the reduction in ischaemic damage.     

The potential role for CDC42 protein from rat brain cytosol in phospholipase D activation

Phospholipase D (PLD) has been extracted from rat brain membranes and chromatographically enriched 70-fold. From the rat brain cytosol, Cdc42 with a Mr of about 24,000 and ADP-ribosylation Factor (Arf) with a Mr of about 18,000 have been purified to near homogeneity. PLD was activated better by purified cytosolic Arf than by the other small G proteins tested. Cdc42 purified from rat brain cytosol showed 70% of PLD activation activity exerted by cytosolic Arf, suggesting that Cdc42 may be one of the major G proteins involved in the activation of membrane-associated PLD. While Cdc42 or RhoA exhibited synergistic activation of PLD when administered in conjunction with Arf, Cdc42 and RhoA showed an additive effect when used together. It is possible that Arf and Rho family proteins may have different interaction sites on PLD. These findings support a role for GTP-binding proteins of the Rho family as well as Arf in the activation of membrane-associated PLD and further suggest that Cdc42 may be a major G protein involved in the PLD activation in rat brain.     

Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide

Over 50% of patients with newly diagnosed rhabdomyosarcoma (RMS) are in the 'intermediate risk' group with a 3-year progression-free survival of approximately 65%. This group consists of stage 1, group III, non-orbit tumours; stage 2, group II and III; and all stage 3 patients utilising the Intergroup Rhabdomyosarcoma Study (IRS) staging system. The role of doxorubicin in the treatment of RMS has been controversial. Ifosfamide, both alone and in combination with etoposide, has significant activity in patients with RMS. The aim of this pilot study was to examine the efficacy and toxicity of a chemotherapy regimen of alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide for intermediate risk RMS. 30 patients with intermediate risk RMS or undifferentiated sarcoma (US) were treated with alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and etoposide/ifosfamide (EI) at planned intervals of 3 weeks. Local treatment of the tumour in most cases was performed after four cycles of chemotherapy, followed by an additional 10 cycles of chemotherapy. At a median follow-up of 37.5 months, the Kaplan-Meier estimate of 3-year event-free survival was 85% (95% confidence interval 72-99%). The overall survival at 3 years was 91% (95% confidence interval 80-100%). No patient died from toxicity. The most common toxicity was febrile neutropenia in 35% of VDC and 26% of EI cycles. No nephrotoxicity or cardiac toxicity was seen. No patient progressed prior to week 12 local therapy. Alternating cycles of VDC and EI are an effective treatment for patients with intermediate risk RMS and US. Toxicity is tolerable. Delaying local treatment until week 12 does not compromise outcome.     

Fluoride pharmacokinetics and changes in lumbar spine and hip bone mineral density

Debate about the use of fluoride for the treatment of vertebral osteoporosis has centered not only on whether fluoride treatment decreases vertebral fractures, but also the interindividual vertebral bone mineral density (BMD) response, the potential for nonvertebral fractures, as well as side effects and tolerability. These effects may be dose dependent and, in this study, we examine the pharmacokinetics of sodium monofluorophosphate (MFP) in osteoporotic patients and relate this to changes in BMD. Plasma fluoride absorption curves were measured from 0 to 6 h after ingestion of MFP at baseline and during long-term dosing in 21 patients with vertebral osteoporosis (T scores < or = 2). BMD was measured at baseline and at 12 months at the lumbar spine (LS), femoral neck (FN), trochanter, and Ward's triangle. We found that fluoride elimination was inversely related to creatinine clearance. LS BMD increased from a median of 0.77 g/cm2 (range 0.69 to 0.99) at baseline to 0.88 g/cm2 (0.75 to 1.13) (p < 0.001) after 12 months. This equates to a median increase of 12% (range -1.2 to 37). Median femoral neck BMD decreased from 0.75 g/cm2 (0.62 to 0.94) at baseline to 0.69 g/cm2 (0.62 to 0.92) (p = 0.13) after 12 months. This equates to a decrease of -2% (-19 to 10). BMD at the other hip sites also decreased slightly. Changes in LS and FN BMD were not significantly related (r = 0.28, p = 0.29). The various pharmacokinetic parameters measured were not related to changes in LS BMD; however, there was an inverse relationship between trough fluoride concentration during long-term dosing and change in FN BMD. Further studies are required to see if this relationship can be used to monitor osteoporotic patients treated with fluoride and prevent significant decreases in FN BMD and possibly fractures at this site.     

CDK4 down-regulation induced by paclitaxel is associated with G1 arrest in gastric cancer cells

Paclitaxel induces a cell cycle block at G2-M phase by preventing the depolymerization of microtubules and induces p53-independent apoptosis in many cancer cells. We observed that gastric cancer cells treated with paclitaxel have shown a cyclin-dependent kinase (CDK)4 down-regulation. This paclitaxel-induced CDK4 down-regulation resulted in a cell cycle arrest at G1-S phase. To confirm this observation, we prepared stable transfectants that overexpressed CDK4 and analyzed the cell cycle progression. Ectopic expression of CDK4 in SNU cells resulted in a release of paclitaxel-induced G1 arrest. The release of G1 arrest by enforced expression of CDK4 seems to make the cells more sensitive to paclitaxel-induced apoptosis. From this finding, we could then suggest that paclitaxel treatment induces both G1-S and G2-M blocks in the cell cycle progression of gastric cancer cells.     

Immune and physiological responses of turkeys with green-liver osteomyelitis complex

A study of field turkeys was undertaken in order to determine the involvement of relative immunological differences in the etiology of turkey osteomyelitis complex (TOC). Lame and normal turkeys were sampled from commercial flocks just prior to processing in two separate trials. After testing for functions of both humoral and cellular immunity, the turkeys were necropsied and examined for lesions of TOC. There were significantly higher relative spleen and over weights and significantly lower body weights and relative bursal weights in birds with TOC. The birds with TOC had lower response to phytohemagglutinin-P in both in vivo and in vitro tests as well as lower circulating lymphocyte counts and higher monocyte, heterophil, and total white blood cell counts. There was a significantly higher antibody response to sheep red blood cells in turkeys with TOC, whereas antibody response to Salmonella pullorum antigen was not different. There were no significant differences in the percentages of mononuclear cells or heterophils able to phagocytize bacteria or latex particles, or kill bacteria; however, the heterophils from turkeys with TOC lesions did phagocytize significantly fewer latex particles per cell than did those of the healthy turkeys. Total serum protein, uric acid, and blood urea nitrogen levels were higher in birds with TOC, whereas hemoglobin, iron, alkaline phosphatase, and gamma-glutamyl-transferase levels were lower. Although many of the differences in birds with TOC could be caused by the normal host reaction to infection, further study may reveal innate differences that contribute to susceptibility to TOC.     

Body mass index and the risk of cancers of the gastric cardia and distal stomach in Shanghai, China

The divergent incidence patterns of gastric cardia and distal stomach cancers suggest different etiologies. Although obesity has recently been linked to cardia cancer in Western populations, its association with distal stomach cancer remains unclear. This study examined the relation of anthropometric measurements to risk by subsites of stomach cancer in a Chinese population. We identified 1124 population-based cases of stomach cancer, ages 20-69 years, newly diagnosed between December 1988 and November 1989 in Shanghai, China. Controls (n = 1451) were randomly selected from permanent Shanghai residents and frequency-matched to cases by age and sex. Information on demographic characteristics, height and weight, diet, smoking, and other exposures was obtained by trained interviewers in person. The body mass index (BMI) was calculated as weight in kilograms divided by height in square meters and categorized into quartiles based on the distribution among controls. Odds ratios and 95% confidence intervals were estimated using logistic regression models, simultaneously adjusting for age, education, income, cigarette smoking (men only), alcohol drinking (men only), intake of total calories, and chronic gastric diseases. For gastric cardia cancer, the odds ratios among men were 1.4, 1.5, and 3.0 in the second, third, and fourth quartiles of usual BMI (P for trend, < 0.01). Among women, elevated risks also were associated with excess weight, but the gradient in risk was not smooth. Risk patterns for usual body weight, maximum BMI, and minimum BMI were similar to those found for usual BMI. For distal stomach cancer, no association with usual BMI was observed among men, but a slightly elevated risk was seen among women. Our observations in China support recent findings in Western populations that obesity contributes to the risk of gastric cardia cancer, especially among men.