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PubMed2006

Extended, one-stage callosal section for treatment of refractory secondarily generalized epilepsy in patients with Lennox-Gastaut and Lennox-like syndromes.

PURPOSE: We report on the efficacy and safety of extended one-stage callosal section performed in a large and homogeneous series of patients. METHODS: Seventy-six patients with Lennox-Gastaut (n = 28) and Lennox-like (n = 48) syndrome were studied (42 male patients; mean age, 11.2 years). All patients had multiple seizure types per day, including atonic, tonic-clonic, atypical absence, myoclonic, and tonic seizures. All of them were developmentally impaired. The EEG showed intense secondary bilateral synchrony in all of them. All patients were submitted to an extended, one-stage, callosal section, leaving only the splenium intact. Mean follow-up time was 4.7 years. RESULTS: Worthwhile improvement (>50%) was noted in 69 of 76 patients; 52 patients had a > or =90% reduction in seizure frequency. Seven patients were seizure free after surgery. The seizure patterns most responsive to surgery were atonic (92%), atypical absence (82%), and tonic-clonic (57%) seizures. All patients had some degree of a transient acute postoperative disconnection syndrome. A consistent increase in attention level was observed postoperatively. CONCLUSIONS: We report one of the larger homogeneous series of patients submitted to callosotomy and are the first to report on the effectiveness and safety of performing extended callosal section in a single stage in this patient group. Extended callosal section should be considered a good palliative surgical option for suitable candidates. The increase in attention level was as useful as seizure control in improving quality of life of these patients.

Attention↗

PubMed2006

Clinical Experience Acquired with Raptiva (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: results from extended treatment in an international, Phase III, placebo-controlled trial.

BACKGROUND: The 12-week, double-blind, placebo-controlled, first-treatment (FT) CLEAR trial period demonstrated the efficacy/safety of efalizumab in moderate-to-severe plaque psoriasis, including refractory or contraindicated patients unsuitable for other systemic treatments. This study assessed the efficacy/safety of open-label extended treatment (up to 24 weeks' continuous treatment) in patients not achieving > or =75% improvement in Psoriasis Area and Severity Index (PASI-75) at week 12 of the FT period. Time to relapse after treatment cessation, and efficacy/safety of 12 weeks' open-label re-treatment in patients achieving PASI-75 at week 12 FT were also assessed. PATIENTS AND METHODS: Patients with PASI-75 at week 12 FT were observed without treatment until relapse, then re-treated with open-label efalizumab (1.0 mg/kg/week for 12 weeks). Others received open-label extended treatment without intervening observation. RESULTS: Among efalizumab-treated patients (n = 308) who had < 75% PASI improvement at week 12 FT, extended treatment led to PASI-75 in 26.6%. Among patients with between > or = 50 and < 75% PASI improvement at week 12 FT (n = 118), 47.5% improved to PASI-75 with extended treatment. For patients achieving PASI-75 at week 12 FT (n = 164), median time to relapse was 58 days. Re-treatment after relapse led to mean PASI improvement of 62.3% from study baseline (n = 145). Safety results were consistent with previous studies, with no new safety concerns. CONCLUSIONS: These results demonstrate additional benefit of continuing efalizumab. Re-treatment re-established disease control in patients with PASI-75 who relapsed following treatment cessation. The safety profile remained consistent with that seen at 12 weeks.

Administration, Topical↗

PubMed1991

Extended HLA-DQw2 haplotypes: molecular analysis.

The HLA-DQw2 specificity, homogeneous in serology, is strongly associated to two HLA-DR specificities: DR3 and DR7. These alleles are found mainly on DQw2 bearing extended haplotypes with strong linkage disequilibrium. We describe, with BamHI, HindIII and RsaI, two restriction fragments length polymorphisms (RFLP) for the A gene of DQw2. These two subtypes correlated with the DR3 and DR7 specificities. Interestingly, by non-equilibrium pH gradient electrophoresis (NEPHGE), two DQ alpha chains were also found, respectively correlated with the same DR specificities. In addition, HincII polymorphism allowed us to distinguish several patterns of B genes for (DR7) DQw2 haplotypes but without any detectable association with another HLA marker. However, only one DQ beta chain was found by NEPHGE in the (DR7) DQw2 haplotype. Furthermore, HincII discriminated the B genes of the two extended haplotypes: (B8, DR3) DQw2 and (B18, DR3) DQw2. The same result was found by NEPHGE: two DQ beta chains were described, corresponding to the same extended haplotypes. The use of exon-specific DQB probes showed that the genomic polymorphism in DQw2 haplotypes is located, at least, at the 3' end of the gene. These data add new characteristics to the different DQw2 extended haplotypes.

Cell Line↗

PubMed1999

The concepts of the ventral striatopallidal system and extended amygdala.

The concepts of the ventral striatopallidal system and extended amygdala have significantly improved our understanding of basal forebrain organization. As a result of these and other advances during the last twenty years, many of the most prominent basal forebrain structures, including the nucleus accumbens, olfactory tubercle, and amygdaloid body, have all but lost their relevance as independent functional anatomical units. In order to appreciate the distinct differences that exist between the ventral striatopallidal system and the extended amygdala, and as a way of explaining the choice of the terms ventral striatopallidal system and extended amygdala, we will review the discovery and subsequent elaboration of these two systems. On the background of these discussions, we will then proceed to dispel some recently published misgivings regarding the usefulness of the extended amygdaloid concept.

Amygdala↗

PubMed1999

The role of the striatopallidal and extended amygdala systems in drug addiction.

Evidence suggests that the acute reinforcing actions of drugs of abuse may be mediated by specific elements of the striatopallidal and extended amygdala systems. These include the shell of the nucleus accumbens, the central nucleus of the amygdala, and the sublenticular extended amygdala. Chronic administration of drugs of abuse, including cocaine, amphetamines, nicotine, alcohol, and tetrahydrocannabinol leads to an increasing dysregulation of brain reward systems that is characterized by decreases in reward function. Withdrawal from chronic administration of cocaine, amphetamine, nicotine, alcohol, and tetrahydrocannabinol raises thresholds for brain stimulation reward. Neurochemical elements in the extended amygdala may mediate these changes, including decreases in dopamine and serotonin neurotransmission in the nucleus accumbens and increases in the brain-stress neurotransmitter, corticotropin-releasing factor, in the central nucleus of the amygdala. The combination of decreases in function of neurotransmitters involved in the positive-reinforcing properties of drugs of abuse with recruitment of brain-stress systems within the extended amygdala provides a powerful mechanism for allostatic changes in hedonic set point that can lead to the compulsive drug-seeking and drug-taking behavior characteristic of addiction.

Amygdala↗

PubMed2002

The cost of transport in an extended trot.

We hypothesised that trotters during an extended trot have lower energetic costs of locomotion (CT) than horses not bred for this behaviour. VO2 was measured as a function of speed in 7 Arabian horses (3 trained to extend their trotting speeds) and in 2 horses, of similar mass, bred to trot (Hackney). Both oxygen consumption and CT increased with speed and there was, contrary to our hypothesis, no difference between breeds. In Arabians at 6.5 m/s, CT had increased 25% above the CT at 5.0 m/s (normal transition speed). For Hackneys at 6.8 m/s, the CT was almost 35% higher. Stride frequencies increased linearly in all horses up to 5.0 m/s. At the canter at 5.0 m/s, the frequency increased 9% to 111 strides/min, but then increased minimally with speed. In the Hackneys and the Arabians that extended the trot, stride frequencies were approximately 102 and did not increase with speed. Stride length (SL) increased linearly with speed in both trotting and cantering horses, and cantering SL were lower than trotting (at 5.0 m/s, SL for trotting = 3.04 m and for cantering SL = 2.68 m). There were no differences between breeds in stride frequency or stride length. Extending the trot can have profound energetic requirements that could limit athletic performance and may lead to increased concussive impact on the limbs.

Animals↗

PubMed1996

Bioavailability and in-vitro/in-vivo correlation for propranolol hydrochloride extended-release bead products prepared using aqueous polymeric dispersions.

The influence of formulation and extrinsic factors has been investigated for the in-vitro release of propranolol hydrochloride from controlled-release beads prepared using aqueous polymeric dispersions, Aquacoat and Surelease. A single-dose three-way crossover bioavailability study of two extended-release experimental formulations (80 mg), Inderal LA (80 mg) and an Inderal immediate-release dosage form (2 x 40 mg) was also conducted and a comparative analysis of pharmacokinetic parameters and the in-vitro release profiles was performed to assess in-vitro/in-vivo correlation. Analysis showed that the in-vitro release data appeared to follow zero-order release kinetics. Intensity of agitation and dissolution method were found to have no significant effect on drug release from beads prepared using either of the coating dispersions studied or Inderal LA. Release of drug from beads coated with Aquacoat was faster in basic media than in acidic media; Surelease-coated beads, however, showed release characteristics that were less sensitive to changes in the pH of the dissolution fluid, and Inderal LA beads showed slower release profiles in acidic medium than in other dissolution media studied. Pharmacokinetic analysis of the data revealed sustained-release absorption characteristics without any evidence of dose-dumping from any of the extended-release dosage forms studied. Regression analysis of the fraction of drug absorbed against the percentage of the drug released in-vitro, at the corresponding times, yielded good in-vitro/in-vivo correlation (level A) for all the extended-release formulations studied. The results showed that there was no dose-dumping from any of extended-release formulations and that the relative bioavailabilities of the experimental formulations were superior to that of the marketed formulation.

Adrenergic beta-Antagonists↗

PubMed2006

Extended speech intelligibility index for the prediction of the speech reception threshold in fluctuating noise.

The extension to the speech intelligibility index (SII; ANSI S3.5-1997 (1997)) proposed by Rhebergen and Versfeld [Rhebergen, K.S., and Versfeld, N.J. (2005). J. Acoust. Soc. Am. 117(4), 2181-2192] is able to predict for normal-hearing listeners the speech intelligibility in both stationary and fluctuating noise maskers with reasonable accuracy. The extended SII model was validated with speech reception threshold (SRT) data from the literature. However, further validation is required and the present paper describes SRT experiments with nonstationary noise conditions that are critical to the extended model. From these data, it can be concluded that the extended SII model is able to predict the SRTs for the majority of conditions, but that predictions are better when the extended SII model includes a function to account for forward masking.

Adolescent↗

PubMed1997

OXA-18, a class D clavulanic acid-inhibited extended-spectrum beta-lactamase from Pseudomonas aeruginosa.

Clinical isolate Pseudomonas aeruginosa Mus showed resistance both to extended-spectrum cephalosporins and to aztreonam. We detected a typical double-disk synergy image when ceftazidime or aztreonam was placed next to a clavulanic acid disk on an agar plate. This resistance phenotype suggested the presence of an extended-spectrum beta-lactamase. Isoelectric focusing revealed that this strain produced three beta-lactamases, of pI 5.5, 7.4, and 8.2. A 2.6-kb Sau3A fragment encoding the extended-spectrum beta-lactamase of pI 5.5 was cloned from P. aeruginosa Mus genomic DNA. This enzyme, named OXA-18, had a relative molecular mass of 30.6 kDa. OXA-18 has a broad substrate profile, hydrolyzing amoxicillin, ticarcillin, cephalothin, ceftazidime, cefotaxime, and aztreonam, but not imipenem or cephamycins. Its activity was totally inhibited by clavulanic acid at 2 microg/ml. Hydrolysis constants of OXA-18 (Vmax, Km) confirmed the MIC results. Cloxacillin and oxacillin hydrolysis was noticeable with the partially purified OXA-18. The blaOXA-18 gene encodes a 275-amino-acid protein which has weak identity with all class D beta-lactamases except OXA-9 and OXA-12 (45 and 42% amino acid identity, respectively). OXA-18 is likely to be chromosomally encoded since no plasmid was found in the strain and because attempts to transfer the resistance marker failed. OXA-18 is peculiar since it is a class D beta-lactamase which confers high resistance to extended-spectrum cephalosporins and seems to have unique hydrolytic properties among non-class A enzymes.

Amino Acid Sequence↗

PubMed2003

Extended-spectrum cephalosporin compared to cefazolin for treatment of Klebsiella pneumoniae-caused liver abscess.

From January 1995 to May 2000, a total of 107 adults with liver abscess due to Klebsiella pneumoniae admitted at a large medical center in northern Taiwan were reviewed. Patients were considered to have received cefazolin or an extended-spectrum cephalosporin if they received at least 3 days of that antibiotic within the first 5 days of hospitalization. Fifty-nine (55.1%) patients received cefazolin, and 48 (44.9%) patients received an extended-spectrum cephalosporin. The demographic data, clinical features, severities of illness, and rates of early drainage for the two groups were comparable. However, the rates of developing complications for the two groups were significantly different (37.3 versus 6.3%, respectively; P < 0.001). Furthermore, six independent factors preventing severe complications following liver abscess due to K. pneumoniae were identified: normal platelet count, alkaline phosphatase less than 300 U/liter, no gas formation in the abscess, APACHE III score less than 40, use of an extended-spectrum cephalosporin, and early drainage. In conclusion, cefazolin therapy may be suboptimal for patients with liver abscess due to K. pneumoniae despite active in vitro susceptibility. Use of an extended-spectrum cephalosporin and early drainage for patients with liver abscess due to K. pneumoniae are suggested.

APACHE↗

PubMed2003

Extended-spectrum beta-lactamases in enterobacteriaceae in Buenos Aires, Argentina, public hospitals.

Resistance to extended-spectrum cephalosporins is often associated with plasmid encoded extended spectrum beta-lactamases (ESBL). In order to evaluate the prevalence and diversity of ESBLs in enterobacteria in our city, a 1-month-period survey was carried out from April to May 2000. Extended-spectrum-cephalosporin-resistant strains, isolated from inpatient clinical specimens other than stools, were collected among 17 participating hospitals. From a total of 427 enterobacterial strains that were collected during this period, 39 were extended-spectrum cephalosporin resistant. The National Committee for Clinical Laboratory Standards' Screening and Confirmatory Tests for ESBL production were performed using cefotaxime and ceftazidime; cefepime and cefepime-clavulanic acid-containing disks were included. beta-Lactamases were characterized by isoelectric focusing and PCR amplification using specific primers. Three different ESBLs were detected: SHV-related (4 isolates), PER-2-type (9 isolates), and CTX-M-2-related (26 isolates). Sequencing of the corresponding genes confirmed CTX-M-2 in 19 of 21 and CTX-M-31 (an allelic variant) in the remaining 2 of 21. CTX-M-2 (or its variant) was detected in all Escherichia coli, Enterobacter aerogenes, Serratia marcescens, Proteus mirabilis, and Providencia stuartii strains, while PER-2 was detected in Enterobacter cloacae, E. aerogenes, and Klebsiella pneumoniae; SHV-related ESBL were found only in K. pneumoniae. These results clearly show that CTX-M-2 is the most prevalent ESBL produced by enterobacterial species isolated from public hospitals in Buenos Aires.

Argentina↗

PubMed2005

Extended-spectrum beta-lactamases: a clinical update.

Extended-spectrum beta-lactamases (ESBLs) are a rapidly evolving group of beta-lactamases which share the ability to hydrolyze third-generation cephalosporins and aztreonam yet are inhibited by clavulanic acid. Typically, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these beta-lactamases. This extends the spectrum of beta-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described. The presence of ESBLs carries tremendous clinical significance. The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates. There is substantial debate as to the optimal method to prevent this occurrence. It has been proposed that cephalosporin breakpoints for the Enterobacteriaceae should be altered so that the need for ESBL detection would be obviated. At present, however, organizations such as the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) provide guidelines for the detection of ESBLs in klebsiellae and Escherichia coli. In common to all ESBL detection methods is the general principle that the activity of extended-spectrum cephalosporins against ESBL-producing organisms will be enhanced by the presence of clavulanic acid. ESBLs represent an impressive example of the ability of gram-negative bacteria to develop new antibiotic resistance mechanisms in the face of the introduction of new antimicrobial agents.

Anti-Bacterial Agents↗

PubMed1994

Adsorption of bacteriophage lambda on the LamB protein of Escherichia coli K-12: point mutations in gene J of lambda responsible for extended host range.

LamB is the cell surface receptor for bacteriophage lambda. LamB missense mutations yielding resistance to lambda group in two classes. Class I mutants block the growth of lambda with the wild-type host range (lambda h+) but support the growth of one-step host range mutants (lambda h). Class II mutants block lambda h but support the growth of two-step host range mutant (lambda hh*) phages. To identify amino acid residues in the J protein (the tail fiber of phage lambda) responsible for the extended host range phenotype of mutants of phage (lambda h+), we selected a series of one-step (lambda h) and two-step (lambda hh*) host range mutants and analyzed their corresponding J genes. Three different class I LamB missense mutants (mutations at sites 247, 245, and 148) were used to select 11 independent, new, one-step host range mutants (lambda h phages). DNA sequence analysis revealed a single-amino-acid change in each case. The 11 alterations affected only three residues in the distal part of J, corresponding to a Val-->Ala change at site 1077 in five cases, a Thr-->Met change at site 1040 in three cases, and a Leu-->Pro change at site 1127 in three cases. Recombination experiments confirmed that in the cases tested, the mutations identified were indeed responsible for the extended host range phenotype. The class II LamB mutant (Gly-->Asp at site 151) was used to select two-step extended host range mutants (lambda hh* phages) from three new lambda h phages, corresponding to different amino acid modifications in the J protein (at sites 1040, 1077, and 1127). The new lambda hh* phages analyzed corresponded to either double or triple point mutations located at the distal end of the J protein. In all, seven residues involved in the extended host range properties of lambda mutants were identified in the distal part of the J protein, suggesting that the last C-terminal portion of the J protein participates directly in the adsorption of the phage onto LamB. In agreement with the fact that the lambda h mutants (and the lambda hh* mutants) could grow on all of the lamB class I mutations tested, we found tha the nature of the J mutations did not depend on the LamB class I mutant used to select them. This is interpreted as meaning that the mutated residues in the J protein and in the LamB mutants are not involved in allele-specific protein-protein interactions. Rather, the LamB mutations would block a step in phage adsorption, and this block would be overcome by the mutations in the J protein.

Adsorption↗

PubMed2005

Extended -10 motif is critical for activity of the cspA promoter but does not contribute to low-temperature transcription.

Bacterial promoters belonging to the extended -10 class contain a conserved TGn motif upstream of the -10 promoter consensus element. Open promoter complexes can be formed on some extended -10 Escherichia coli promoters at temperatures as low as 6 degrees C, when complexes on most promoters are closed. The promoter of cspA, a gene that codes for the major cold shock protein CspA of E. coli, contains an extended -10 motif. CspA is dramatically induced upon temperature downshift from 37 to 15 degrees C, and its cold shock induction has been attributed to transcription, translation, and mRNA stabilization effects. Here, we show that though the extended -10 motif is critical for high-level expression of cspA, it does not contribute to low-temperature expression. In fact, transcription from the wild-type cspA promoter is cold sensitive in vitro and in vivo. Thus, transcription appears to play little or no role in low-temperature induction of cspA expression.

Bacterial Proteins↗

PubMed2003

Evaluation of the NCCLS extended-spectrum beta-lactamase confirmation methods for Escherichia coli with isolates collected during Project ICARE.

To determine whether confirmatory tests for extended-spectrum beta-lactamase (ESBL) production in Escherichia coli are necessary, we selected 131 E. coli isolates that met the National Committee for Clinical Laboratory Standards (NCCLS) screening criteria for potential ESBL production from the Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology) strain collection. For all 131 isolates, the broth microdilution (BMD) MIC of at least one extended-spectrum cephalosporin was >/=2 micro g/ml. For 21 of 131 (16%) isolates, the ESBL confirmatory test was positive; i.e., the BMD MICs of ceftazidime or cefotaxime decreased by >/=3 doubling dilutions in the presence of clavulanic acid (CA) or the disk diffusion zone diameters increased by >/=5 mm around ceftazidime or cefotaxime disks in the presence of CA. All 21 isolates were shown by PCR to contain at least one of the genes bla(TEM), bla(SHV), and bla(OXA), and in isoelectric focusing (IEF) tests, all isolates demonstrated at least one beta-lactamase band consistent with a TEM, SHV, or OXA enzyme. Of the 21 isolates, 3 showed a CA effect for cefotaxime by BMD but not by disk diffusion testing. A total of 59 (45%) of the 131 isolates demonstrated decreased susceptibility to cefpodoxime alone (MIC = 2 to 4 micro g/ml), and none had a positive ESBL confirmatory test result. These were classified as false positives according to ESBL screen test results. For the remaining 51 (39%) isolates, the cefpodoxime MICs ranged from 16 to >128 micro g/ml and the MICs for the other extended-spectrum cephalosporins were highly variable. All 51 isolates gave negative ESBL confirmatory test results. Most showed IEF profiles consistent with production of both a TEM and an AmpC beta-lactamase, and representative isolates of several phenotypic groups showed changes in porin profiles; these 51 isolates were considered true negatives. In all, only 16% of 131 E. coli isolates identified as potential ESBL producers by the current NCCLS screening criteria were confirmed as ESBL producers. Thus, changing the interpretation of extended-spectrum cephalosporins and aztreonam results from the susceptible to the resistant category without confirming the presence of an ESBL phenotype would lead to a large percentage of false resistance results and is not recommended. However, by increasing the cefpodoxime MIC screening breakpoint to >/=8 micro g/ml, 45% of the false-positive results could be eliminated. NCCLS has incorporated this change in the cefpodoxime screening breakpoint in its recent documents.

Anti-Bacterial Agents↗

PubMed2003

Yeast DNA polymerase zeta is an efficient extender of primer ends opposite from 7,8-dihydro-8-Oxoguanine and O6-methylguanine.

Genetic studies in Saccharomyces cerevisiae have indicated the requirement of DNA polymerase (Pol) zeta for mutagenesis induced by UV light and by other DNA damaging agents. However, on its own, Pol zeta is highly inefficient at replicating through DNA lesions; rather, it promotes their mutagenic bypass by extending from the nucleotide inserted opposite the lesion by another DNA polymerase. So far, such a role for Pol zeta has been established for cyclobutane pyrimidine dimers, (6-4) dipyrimidine photoproducts, and abasic sites. Here, we examine whether Pol zeta can replicate through the 7,8-dihydro-8-oxoguanine (8-oxoG) and O(6)-methylguanine (m6G) lesions. We chose these two lesions for this study because the replicative polymerase, Pol delta, can replicate through them, albeit weakly. We found that Pol zeta is very inefficient at inserting nucleotides opposite both these lesions, but it can efficiently extend from the nucleotides inserted opposite them by Pol delta. Also, the most efficient bypass of 8-oxoG and m6G lesions occurs when Pol delta is combined with Pol zeta, indicating a role for Polzeta in extending from the nucleotides inserted opposite these lesions by Pol delta. Thus, Pol zeta is a highly specialized polymerase that can proficiently extend from the primer ends opposite DNA lesions, irrespective of their degree of geometric distortion. Pol zeta, however, is unusually sensitive to geometric distortion of the templating residue, as it is highly inefficient at incorporating nucleotides even opposite the moderately distorting 8-oxoG and m6G lesions.

Base Sequence↗

PubMed2005

Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis.

OBJECTIVES: To review the evidence from controlled clinical trials of neonates given equal daily aminoglycoside doses as extended interval dosing (dosage interval typically 24 hours in term and 36-48 hours in immature neonates) compared with traditional dosing (dosage interval typically 8-12 hours in term and 12-24 hours in immature neonates). DESIGN: Systematic review and meta-analysis of controlled trials found in electronic databases, trial registers, and references in reviews and selected trials. SETTINGS: The selected trials were blinded and assessed for methodological quality. Each trial's own predefined criteria for treatment failure, nephrotoxicity, ototoxicity, and therapeutic serum drug concentrations were used. SUBJECTS: Controlled trials of neonatal aminoglycoside treatment in which equal aminoglycoside daily doses were given at traditional and extended dosage intervals. MAIN OUTCOME MEASURES: Serum drug concentrations outside the therapeutic range. Treatment failure and toxicity. RESULTS: Sixteen trials involving 823 neonates met the inclusion criteria for the systematic review. Twelve trials involving 698 neonates were included in the meta-analysis of the pharmacokinetics. Compared with traditional dosing, extended interval dosing was associated with a significantly lower risk of both peak (summary risk ratio 0.50, 95% confidence interval 0.26 to 0.94) and trough (0.36, 0.25 to 0.56) serum drug concentrations outside the therapeutic range. Accurate information on treatment failure was obtained in nine trials involving 555 neonates. One trial reported treatment failure. In this trial two neonates in the traditional dosing group did not respond to treatment within 72 hours. Nephrotoxicity was investigated in 589 neonates in 12 trials and ototoxicity in 210 neonates in four trials, with no significant differences between the two dosing regimens. CONCLUSIONS: Extended interval dosing of aminoglycosides in neonates is safe and effective, with a reduced risk of serum drug concentrations outside the therapeutic range.

Aminoglycosides↗

PubMed1992

Extended fetal echocardiographic examination for detecting cardiac malformations in low risk pregnancies.

OBJECTIVE: To improve the rate of prenatal detection of cardiac malformations in a low risk population. DESIGN: Comparison of extended fetal echocardiography with the standard four chamber view in detecting abnormalities. Extended echocardiography comprised the four chamber view and visualisation of the left ventricular outflow tract, the right ventricular outflow tract, and the main pulmonary artery and its branches. In cases with abnormal results complete echocardiographic studies were performed by a paediatric cardiologist using M mode, Doppler, and colour flow mapping techniques. SETTING: Obstetric ultrasonographic unit at Shaare-Zedek Medical Centre, Jerusalem. SUBJECTS: 5400 fetuses in low risk pregnancies between 18 and 24 weeks' gestation (mean 21 weeks); 53 were lost to follow up. MAIN OUTCOME MEASURES: Detection of abnormality before and after birth. RESULTS: During the study 23 infants (0.4%) were born with cardiac abnormalities, 21 of whom had major structural and functional heart disease. 18 fetuses had heart disease diagnosed prenatally, 11 by the four chamber view alone (sensitivity 48%) and a further seven by extended echocardiography (sensitivity 78%). Five fetal cardiac defects were missed prenatally (false negative rate 22%). These included coarctation of aorta, persistent truncus arteriosus, tetralogy of Fallot, ventricular septal defect, and pulmonic stenosis. Only one false positive diagnosis (coarctation of aorta) was made (specificity 99.9%, false positive rate 0.1%). The abnormality was correctly identified in 17 out of 18 cases. CONCLUSIONS: The extended fetal heart examination detected 86% (18/21) of major abnormalities in a low risk population. The examination should be incorporated into routine prenatal ultrasonographic investigations.

Adolescent↗