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PubMed1992

Superficial extending carcinoma (SEC) of the larynx and hypopharynx.

In this study the histopathological features of an underestimated architectural variety of infiltrating squamous cell carcinoma of the larynx and hypopharynx, operationally termed as "superficial extending carcinoma", are described. Pathologically, the superficial extending carcinoma is a poorly/moderately differentiated infiltrating squamous cell carcinoma showing an entirely or predominant superficial type of growth; deep infiltration was confined to the mucosa or limited to a few underlying glandular and/or muscular laryngopharyngeal structures, regardless of the presence of lymph node metastasis or lymph vessel invasion. As defined above, the superficial extending carcinoma may be regarded, from a pathologic point of view, as a laryngopharyngeal counterpart to "superficial esophageal carcinoma". Studying a series of 88 whole organs serially sectioned laryngopharyngectomy specimens, we found that 6 out of 61 primary laryngeal carcinomas (9.8%) and 6 out of 26 primary hypopharyngeal carcinomas (23%) showed the peculiar architectural features of the superficial extending carcinoma. In 6 cases (2 laryngeal and 4 hypopharyngeal) the tumor was entirely intramucosal or early infiltrated the underlying muscle or gland structures. In the remaining 6 cases (4 laryngeal and 2 hypopharyngeal tumor) a superficial extending carcinoma was found to be associated with a deeply infiltrating squamous cell carcinoma of the "classic" type. Features useful to histopathologic diagnosis of superficial extending carcinoma and to its differentiation from preneoplastic and other neoplastic lesions of the laryngopharyngeal mucosa are emphasized. The possible association of superficial extending carcinoma with multiple synchronous and metachronous neoplastic lesions in the upper aerodigestive tract and the frequent underestimation of its real extension may have important clinical implications.

Adult↗

PubMed2003

Beyond Medline: reducing bias through extended systematic review search.

OBJECTIVE: To evaluate the sensitivity and precision of various extended search methods in identifying randomized controlled trials (RCTs) for systematic reviews. METHOD: Prospective analysis of extended search methods (specialized databases or trial registries, reference lists, hand-searching, personal communication, and Internet) used in two systematic reviews of RCTs. The gold standard was the total number of RCTs identified by major databases (MEDLINE, EMBASE, etc.) and extended search strategies combined. Sensitivity was the proportion of all known RCTs identified by any extended search method. Precision reflected the proportion of all items uncovered by any extended search method that actually were RCTs. RESULTS: The extended search identified 94 additional RCTs for the systematic reviews beyond those identified with the major databases. Specialized databases and trial registries had the highest sensitivity and precision for the lipid-lowering project (13.6% and 52.7%, respectively; p < .05) followed by scanning of reference lists (7.2% sensitivity and 41.9% precision; p <.05). Hand-searching was more effective than personal communication and Internet searching (1.7% sensitivity and 12.2% precision; p < .05). The acupuncture project had slightly different results, with the specialized databases and trial registries tied with the review of reference lists for highest sensitivity (14.2%). The precision followed the same trend as the lipid-lowering project (17.6% specialized databases; 8.3% reference lists; p < .05). A post-hoc analysis showed that 75 of the 94 RCTs were indexed in the major databases but missed by the major database search. CONCLUSIONS: Extended searching identified additional RCTs for the systematic reviews beyond those found in major databases. Specialized databases and trial registries were most effective. An important number of RCTs were missed by the major database search. Timing and accuracy of indexing may explain this finding. The definitive measure, whether there is an association between the method used to uncover RCTs, the quality of the items uncovered and their impact on systematic review results, is yet to be determined.

Humans↗

PubMed2003

Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats.

While oral naltrexone is effective in treating alcohol and opiate dependencies, poor patient adherence and widely fluctuating plasma levels limit its efficacy. To overcome these problems, an extended-release formulation of naltrexone (Vivitrex) was developed by encapsulating naltrexone into injectable, biodegradable polymer microspheres. Pharmacokinetic studies in rats demonstrated that this formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately 1 month following either subcutaneous or intramuscular injections. While rats receiving placebo microspheres demonstrated a pronounced analgesic response to morphine in the hot-plate test, morphine analgesia was completely blocked in rats treated with extended-release naltrexone. This antagonism began on day 1 following administration and lasted for 28 days. Rats reinjected with extended-release naltrexone 34 days after the initial dose and tested for another 35 days showed consistent suppression of morphine analgesia for an additional 28 days. mu-Opioid receptor density, as measured by [(3)H]DAMGO autoradiography, increased up to two-fold following a single injection of extended-release naltrexone. Saturation binding assays using [(3)H]DAMGO showed changes in the midbrain and striatum at 1 week after extended-release naltrexone administration, and after 1 month in the neocortex. These receptor increases persisted for 2-4 weeks after dissipation of the morphine antagonist actions of naltrexone. These data suggest that therapeutically relevant plasma levels of naltrexone can be maintained using monthly injections of an extended-release microsphere formulation, and that changes in mu-opioid receptor density do not impact its efficacy in suppressing morphine-induced analgesia in the rat. Clinical trials of extended release naltrexone for treating alcohol and opiate dependency are currently ongoing.

Animals↗

PubMed2001

Extending the general practice training year: experience of one model in Scotland.

OBJECTIVES: These were: to describe the implementation of a scheme to extend the general practice registrar component of vocational training to 18 months in Scotland; to determine the effect of the additional attachment on registrars' confidence and skill deficits, and compare changes in these parameters with a control group of registrars who did not extend their training, and to determine whether trainers required a different training style for experienced registrars. SUBJECTS: 35 registrars extending their training, their trainers, and 39 controls who did not extend their training. SETTING: Scottish training practices. METHODS: Pre-attachment and post-attachment questionnaires for registrars, triangulated by semistructured telephone interviews, and post-attachment questionnaires for trainers. RESULTS: Extended attachments were popular with registrars and with trainers, who felt they should be a normal part of training. Registrars with extended training declared themselves to have increased in confidence and addressed skill deficits better than controls. Projects completed were assessed as being of high quality. Trainers found 10% of registrars to have a remediable, important deficit in their skills. CONCLUSION: Extended attachments appear to improve registrar confidence and to address knowledge deficits. However, only a minority of registrars had important remediable knowledge deficits and while such attachments may be desirable they may not be essential for most registrars. Overall the outcome appears to have been positive, and supports those who have argued for a change in the proportion of time spent in general practice training, but the scheme is expensive and it is difficult to set a value on what has been gained. Future schemes should have clear training objectives and be tailored towards these.

Chi-Square Distribution↗

PubMed2004

[Imaging of the abdominal wall: combination of tissue-harmonic-imaging and extended field-of-view sonography].

PURPOSE: To evaluate the combined use of extended field-of-view sonography and tissue harmonic imaging (THI) for assessment of the abdominal wall. MATERIALS AND METHODS: In 32 patients (25 patients without and 7 patients with abdominal wall pathologies) extended field-of-view sonography of the abdominal wall was performed with and without THI using a 7.5 MHz ultrasound transducer. Images with a scan length of 60 cm were acquired above and below the arcuate line. The images were independently assessed by two observers regarding visibility of the anatomic structures and delineation of pathological changes using a 4-point grading scale. Furthermore, the influence of the extent of the subcutaneous fat on the image quality was assessed. For statistical analysis, kappa coefficients, Fisher"s exact test and a repeated measurement analysis of variance (ANOVA) were applied. RESULTS: In all patients, delineation of the abdominal wall was possible with diagnostic image quality. Abdominal wall pathologies were concurrently diagnosed for extended field-of-view sonography with and without utilization of THI. Image quality was rated better with THI when compared to extended field-of-view B-Mode sonography. In comparison to extended field-of-view B-Mode sonography, the agreement between both readers regarding image quality was markedly improved using extended field-of-view sonography in combination with THI. With increasing thickness of the subcutaneous fat layer, image quality was rated significantly better using THI than B-Mode ultrasound. CONCLUSION: Combined use of extended field-of-view sonography and THI improves image quality and documentation of ultrasound examinations. Especially in obese patients, the use of THI is advantageous. Therefore, abdominal wall ultrasound gains additional value in the preoperative planning.

Abdominal Wall↗

PubMed1986

Major-histocompatibility-complex extended haplotypes in membranoproliferative glomerulonephritis.

Membranoproliferative glomerulonephritis is often associated with evidence of immune derangement, especially hypocomplementemia. We studied genetic markers for membranoproliferative glomerulonephritis within the major histocompatibility complex in 34 patients and their families and in 29 normal families. We examined the frequencies of extended haplotypes (combinations of alleles that tend to occur together) in patients and controls. The extended haplotype HLA-B8,DR3,SC01,GLO2(glyoxalase I 2) was observed in 9 of 68 disease-associated haplotypes (13 percent), but in only 3 of 205 controls (1 percent) (relative risk, 14.79; P less than 0.001). An extended haplotype similar except for a different glyoxalase allotype (B8,DR3,SC01,GLO1) did not occur with increased frequency, nor did any other extended haplotypes. Patients with the extended haplotype B8,DR3,SC01,GLO2 had a higher incidence of renal insufficiency than those without it (P less than 0.01). The data support the hypothesis that a specific extended haplotype of the major histocompatibility complex is associated with susceptibility to membranoproliferative glomerulonephritis, and that patients with glomerulonephritis who have this extended haplotype have a poorer prognosis for kidney survival than those without the haplotype.

Alleles↗

PubMed2005

Extended work shifts and the risk of motor vehicle crashes among interns.

BACKGROUND: Long work hours and work shifts of an extended duration (> or =24 hours) remain a hallmark of medical education in the United States. Yet their effect on health and safety has not been evaluated with the use of validated measures. METHODS: We conducted a prospective nationwide, Web-based survey in which 2737 residents in their first postgraduate year (interns) completed 17,003 monthly reports that provided detailed information about work hours, work shifts of an extended duration, documented motor vehicle crashes, near-miss incidents, and incidents involving involuntary sleeping. RESULTS: The odds ratios for reporting a motor vehicle crash and for reporting a near-miss incident after an extended work shift, as compared with a shift that was not of extended duration, were 2.3 (95 percent confidence interval, 1.6 to 3.3) and 5.9 (95 percent confidence interval, 5.4 to 6.3), respectively. In a prospective analysis, every extended work shift that was scheduled in a month increased the monthly risk of a motor vehicle crash by 9.1 percent (95 percent confidence interval, 3.4 to 14.7 percent) and increased the monthly risk of a crash during the commute from work by 16.2 percent (95 percent confidence interval, 7.8 to 24.7 percent). In months in which interns worked five or more extended shifts, the risk that they would fall asleep while driving or while stopped in traffic was significantly increased (odds ratios, 2.39 [95 percent confidence interval, 2.31 to 2.46] and 3.69 [95 percent confidence interval, 3.60 to 3.77], respectively). CONCLUSIONS: Extended-duration work shifts, which are currently sanctioned by the Accreditation Council for Graduate Medical Education, pose safety hazards for interns. These results have implications for medical residency programs, which routinely schedule physicians to work more than 24 consecutive hours.

Accidents, Traffic↗

PubMed1998

The role of residue 238 of TEM-1 beta-lactamase in the hydrolysis of extended-spectrum antibiotics.

beta-Lactamases inactivate beta-lactam antibiotics by catalyzing the hydrolysis of the amide bond in the beta-lactam ring. The plasmid-encoded class A TEM-1 beta-lactamase is a commonly encountered beta-lactamase. It is able to inactivate penicillins and cephalosporins but not extended-spectrum antibiotics. However, TEM-1-derived natural variants containing the G238S amino acid substitution display increased hydrolysis of extended-spectrum antibiotics. Two models have been proposed to explain the role of the G238S substitution in hydrolysis of extended-spectrum antibiotics. The first proposes a direct hydrogen bond of the Ser238 side chain to the oxime group of extended-spectrum antibiotics. The second proposes that steric conflict with surrounding residues, due to increased side chain volume, leads to a more accessible active site pocket. To assess the validity of each model, TEM-1 mutants with amino acids substitutions of Ala, Ser, Cys, Thr, Asn, and Val have been constructed. Kinetic analysis of these enzymes with penicillins and cephalosporins suggests that a hydrogen bond is necessary but not sufficient to achieve the hydrolytic activity of the G238S enzyme for the extended-spectrum antibiotics cefotaxime and ceftazidime. In addition, it appears that the new hydrogen bond interaction is to a site on the enzyme rather than directly to the extended-spectrum antibiotic. The data indicate that, for the G238S substitution, a combination of an optimal side chain volume and hydrogen bonding potential results in the most versatile and advantageous antibiotic hydrolytic spectrum for bacterial resistance to extended-spectrum antibiotics.

Anti-Bacterial Agents↗

PubMed2003

Kissing complex-mediated dimerisation of HIV-1 RNA: coupling extended duplex formation to ribozyme cleavage.

Initiation of retroviral genomic RNA dimerisation is mediated by the mutual interaction of the dimerisation initiation site (DIS) stem-loops near to the 5' end of the RNA. This process is thought to involve formation of a transient 'kissing' complex over the self-complementary loop bases, which then refolds into a more stable extended interaction. We have developed a novel experimental system that allows us to clearly detect the extended duplex in vitro. Ribozyme sequences were incorporated into or adjacent to the type 1 human immunodeficiency virus DIS stem, leading to the formation of a functional ribozyme only in the extended duplex conformer. Here we show that extended duplex formation results in ribozyme cleavage, thus demonstrating the double-stranded nature of the extended complex and confirming that refolding occurs via melting of the DIS stems. Loop complementarity is essential for extended duplex formation but no sequence requirements for the loops were observed. Efficiency of extended duplex formation is dependent on the strength of the loop-loop interaction, temperature, the magnesium concentration and is strongly accelerated by the viral nucleocapsid protein NCp7. Our ribozyme-coupled approach should be applicable to the analyses of other refolding processes involving RNA loop-loop interactions.

Base Sequence↗

PubMed2001

Life-extending therapies among patients with advanced cancer: patients' levels of pain and family caregivers' concerns about pain relief.

The purposes of this article are to explore the extent to which oncology unit patients with advanced cancer in Taiwan receive life-extending therapies and to examine the relationship of care goals (curative vs palliative) to levels of pain and family caregivers' concerns about pain reporting and analgesic administration. Forty pairs of patients with advanced cancer and their family caregivers (N = 80) were recruited from inpatient oncology units in Taiwan. Of these patients, 53% were receiving chemotherapy or radiotherapy for life-extending or curative reasons as opposed to palliative goals. Patients with advanced cancer who were receiving life-extending therapies experienced lower levels of pain intensity than did those who were not receiving life-extending therapies. Moreover, Taiwanese family caregivers of patients with advanced cancer had concerns about reporting pain and administering analgesics regardless of whether the patient was receiving life-extending therapies. However, the family caregivers whose patients were receiving life-extending therapies were less concerned about using analgesics than were those caregivers whose patients were not receiving life-extending therapies. Finally, family caregivers' concerns about pain management as measured by the Barriers Questionnaire-Taiwan (BQT) form were related to family caregivers' reluctance to report their patients' pain. Implications of this study are discussed in terms of palliative care and pain educational programs.

Adult↗

PubMed2001

Extending inspiratory time in acute respiratory distress syndrome.

OBJECTIVE: To assess the short-term effects of extending inspiratory time by lengthening end-inspiratory pause (EIP) without inducing a clinically significant increase in intrinsic positive end-expiratory pressure (PEEPi) in patients with acute respiratory distress syndrome (ARDS). DESIGN: Controlled, randomized, crossover study. SETTING: Two medical intensive care units of university hospitals. PATIENTS: Sixteen patients with early (< or =48 hrs) ARDS. INTERVENTION: We applied two durations of EIP (0.2 secs and extended) each for 1 hr while keeping all the following ventilatory parameters constant: FIO2, total PEEP (PEEPtot = applied PEEP + PEEPi), tidal volume, inspiratory flow, and respiratory rate. The duration of extended EIP was titrated to avoid an increase of PEEPi of > or =1 cm H2O. MEASUREMENTS AND MAIN RESULTS: Despite an increase in mean airway pressure (20.6 +/- 2.3 vs. 17.6 +/- 2.1 cm H2O, p < .01), extended EIP did not significantly improve PaO2 (93 +/- 21 vs. 86 +/-16 torr [12.40 +/- 2.80 vs. 11.46 +/- 2.13 kPa] with 0.2 secs EIP, NS). However, although the difference in PaO2 between the two EIP durations was <20 torr (<2.66 kPa) in 14 patients, two patients exhibited a >40 torr (>5.33 kPa) increase in PaO2 with extended EIP. Extended EIP decreased PaCO2 (62 +/- 13 vs. 67 +/- 13 torr [8.26 +/- 1.73 vs. 8.93 +/- 1.73 kPa] with 0.2 secs EIP, p < .01), which resulted in a higher pH (7.22 +/- 0.10 vs. 7.19 +/- 0.09 with 0.2 secs EIP, p < .01) and contributed to a slight increase in arterial hemoglobin saturation (94 +/- 3 vs. 93 +/- 3% with 0.2 EIP, p < .01). No significant difference in hemodynamics was observed. CONCLUSION: In patients with ARDS, extending EIP without inducing a clinically significant increase in PEEPi does not consistently improve arterial oxygenation but enhances CO2 elimination.

Adult↗

PubMed2002

Extended incision in open-approach rhinoplasty for asians.

The purpose of this study was to introduce an extended incision in open-approach rhinoplasty for obtaining greater satisfaction in aesthetic rhinoplasty for Asians. This incision is the same as for the usual open rhinoplasty incision, but it is extended along the caudal border of the footplates of the medial crura onto the floor of the nasal vestibule to access the footplates of the medial crura more easily. This simple extended incision enabled the authors to achieve further tip projection because the pressure of the skin flap on the tip was reduced. By approximating the lateral curves of the medial crural footplates, the width and the length of the columella were narrowed and lengthened, respectively. The columella was also advanced caudally; thus, the shape of the nostrils could also be elongated. In addition, a cartilage graft or an implant insertion for alar base augmentation could be performed through this extended incision without an additional incision. Another advantage was that in correction of caudal septal deviation, displaced septal cartilage could be repositioned by suturing to the periosteum or soft tissue around the anterior nasal spine without drilling into it through an intraoral incision. Fifty-one consecutive patients who underwent this extended open-approach rhinoplasty between August of 1999 and September of 2000 were included in this study. A total of 40 patients had an adequate follow-up time of over 6 months. Patient satisfaction and postoperative complications were recorded. The majority of the patients (35 of 40) were satisfied with the results of the procedure. Two patients had complications of nostril-scar contracture requiring close follow-up. There were no cases of implant extrusion, displacement, or infection. No patients experienced transcolumellar or extended-incision scarring. Although further studies and longer follow-up are needed to determine the value of this incision, the authors believe that the addition of the extended incision in open-approach rhinoplasty is safe and reliable for effecting better results for Asians.

Cicatrix↗

PubMed2005

Extended cycle hormonal contraception in adolescents.

PURPOSE OF REVIEW: There is increasing interest in the use of extended cycles of hormonal contraception to manage menstrual cycle-related complaints in adolescents and to accommodate the menstrual preferences of patients using hormonal contraception. This review summarizes recent findings related to the use of extended cycles and highlights their relevance to adolescents. RECENT FINDINGS: Many adolescents would prefer to menstruate less frequently. Among health care providers who prescribe hormonal contraceptives, the majority believe suppressing withdrawal bleeding is well tolerated and prescribe extended cycling regimens to their patients. Shortening or eliminating the hormone-free interval results in greater ovarian suppression and thus may increase contraceptive efficacy. Studies in adult women have not identified changes in metabolic parameters beyond what would be expected from traditional cyclic use. New endometrial biopsy data have found no pathologic changes; most women using an extended cycle had atrophic endometriums. Extended cycling is frequently associated with breakthrough bleeding. In some women, this can be managed with a brief hormone-free interval. SUMMARY: Recent findings demonstrate high levels of interest in extended cycling among adolescents and providers, and continue to add to the growing body of literature supporting the safety and improved contraceptive efficacy of extended regimens. Further research is warranted to focus on issues including cancer, thrombotic disease and fertility, and should enroll a sufficient adolescent sample.

Adolescent↗

PubMed2004

A comparison of extended biopsy and sextant biopsy schemes for predicting the pathological stage of prostate cancer.

PURPOSE: We compared the performance of the extended multisite directed biopsy strategy to the sextant component of this strategy for predicting the pathological stage and Gleason score of the radical prostatectomy specimen. MATERIALS AND METHODS: We studied 157 men in whom prostate cancer was diagnosed by extended multisite directed biopsy and who underwent radical retropubic prostatectomy. The pretreatment variables of serum prostate specific antigen, prostate specific antigen density, biopsy specimen Gleason score, the location, number and percent of cancer containing cores, greatest tumor length in a single core and greatest percent of tumor in a single core were determined and compared with the pathological features of prostate cancer in the radical prostatectomy specimens. A comparison of the information obtained from sextant component cores of the extended biopsy strategy with that from all cores of the extended biopsy strategy was performed using chi-square statistics and ROC curve analysis. RESULTS: When comparing the areas under the ROC curves, the extended multisite directed biopsy strategy was found to have greater predictive power for extraprostatic extension than the sextant core component of this biopsy scheme, although the difference was not significantly different. The sextant component was equivalent to the extended biopsy strategy for predicting the prostatectomy specimen Gleason score. CONCLUSIONS: The extended biopsy strategy has better performance in the upper sensitivity ranges compared to the sextant technique for predicting extraprostatic extension.

Biopsy↗

PubMed2005

Use of extended pattern technique for initial prostate biopsy.

PURPOSE: An extended prostate biopsy schema has been advocated at initial prostate biopsy to decrease the rate of false-negative cancer cases. However, critics have raised concerns that this may lead to the greater detection of clinically insignificant cancers. We examined the impact of using an extended pattern schema on cancer detection and also on the finding of smaller and clinically insignificant cancer. MATERIALS AND METHODS: Clinical data, including patient age, race, prebiopsy prostate specific antigen (PSA), digital rectal examination, prostate volume, number of needle cores and biopsy findings were abstracted from the medical records of all patients who underwent prostate biopsy in a 5-year period. Extended pattern prostate biopsy was defined as more than 10 cores. Clinically insignificant cancer was defined as a maximal tumor dimension of 1.0 cm or less, Gleason sum 6 or less and organ confined disease at radical prostatectomy. Adjusted regression models were developed to assess the independent effects of using an extended biopsy pattern on the detection of cancer overall and on the detection of clinically insignificant cancer. RESULTS: A total of 740 men with a mean age of 62.6 years were referred for prostate biopsy. Median PSA was 5.7 ng/ml and prostate volume was 39.7 cc. The OR for detecting prostate cancer was 1.55 (95% CI 1.09 to 2.19) for the extended pattern compared with standard biopsy. Of the subset of 136 patients who underwent radical prostatectomy 12.6% had clinically insignificant cancer. However, in contrast to overall cancer detection, extended pattern prostate biopsy was not found to be associated with an increased risk of detecting smaller or clinically insignificant cancer. PSA density was the single parameter found to be independently associated with the detection of clinically insignificant cancer (95% CI 0.20 to 0.98). CONCLUSIONS: Using an extended prostate biopsy pattern involving more than 10 cores increases the likelihood of detecting prostate cancer. A significant association between more needle cores at initial prostate biopsy and finding smaller and clinically insignificant cancer was not apparent.

Biopsy, Needle↗

PubMed2005

Outcomes of extended donor lung recipients after lung transplantation.

BACKGROUND: Lung transplantation is currently limited by the number of suitable donor organs. Many lung-transplant programs use lungs that do not meet the formal criteria for acceptability; however, the immediate and long-term consequences of this approach remain unclear. METHODS: We performed a retrospective cohort study of all patients who underwent lung transplantation at the Columbia University Medical Center from July 2001 to July 2003. We assessed the outcomes of recipients of extended donor lungs compared with those of recipients of optimal donor lungs after adjusting for confounding variables. RESULTS: Fifty-one patients underwent lung transplantation, of which 27 (53%) received extended donor lungs. Recipients of extended donor lungs had fewer intensive care unit-free days at 30 days (P=0.002) and a longer time to hospital discharge (P=0.007) than did recipients of optimal donor lungs. Extended donor recipients also had lower forced expiratory volume in 1 second % predicted at 1 year than did optimal donor recipients (P=0.03). There were no differences in the 30-day or longer-term survival of extended and optimal donor lung recipients. CONCLUSIONS: Recipients of extended donor lungs have a longer intensive care unit course, a prolonged hospital stay, and lower pulmonary function at 1 year than recipients of optimal lungs. Despite these differences, survival is similar between the two groups. The criteria for the optimal lung donor should be re-evaluated considering the current shortage of acceptable organs. Although some outcomes may differ with the use of extended donor lungs, the clinical impact of these differences should be assessed in future prospective multicenter studies.

Adult↗

PubMed2003

Human DNA polymerase kappa uses template-primer misalignment as a novel means for extending mispaired termini and for generating single-base deletions.

Human DNA polymerase kappa (hPolkappa) is a proficient extender of mispaired primer termini on undamaged DNA, wherein it extends directly by incorporating the next correct nucleotide, generating single-base substitutions in the process. Biochemical and genetic studies, however, have indicated that, in addition to single-base substitutions, Polkappa generates single-base deletions. Here we show that hPolkappa is very adept at using template-primer misalignment as a novel means for extending mispaired termini and for generating single-base deletions. The proficient ability of hPolkappa to extend mispaired primer termini either directly or by misalignment could be important for the continued and efficient progression of the replication fork when mismatches introduced by the replicative polymerase are not proofread. In extending from nucleotides opposite DNA lesions, hPolkappa uses the direct and misalignment modes of mispair extension to different extents, depending on whether the template base is present or not at the primer terminus; thus, although hPolkappa can extend directly from nucleotides opposite damaged bases, it can use only the misalignment mechanism to extend from nucleotides opposite an abasic site. A particularly unconstrained active site at the template-primer junction could afford hPolkappa the ability to tolerate the geometric distortions of mismatched base pairs or those resulting from template-primer misalignment, thereby enabling it to use both of these modes of mispair extension.

DNA↗

PubMed2005

Extended-release divalproex in child and adolescent outpatients with epilepsy.

PURPOSE: To determine whether valproic acid [divalproex (DVP)] extended-release, administered at a higher proportionate once-daily dosage, can be safely substituted for delayed-release or sprinkle in pediatric patients with epilepsy. METHODS: Patients between ages 6 and 17 years with stable epilepsy taking DVP were randomized to 7 days of either DVP delayed-release/sprinkle (at the usual daily dose taken before study entry) or extended-release DVP (daily dose, 8% to 25% higher than their usual dose), and then (crossed over to) 7 days of the comparator formulation. Patient's clinical status was evaluated at a screening visit and on days 8 and 15, and with telephone follow-up 1 month after study completion. RESULTS: No statistically significant difference in mean plasma VPA levels measured at the end of treatment was observed: 99, 92, and 103 mug/ml with the delayed-release tablets (n = 4), the sprinkle formulation (n = 11), and the extended-release tablets (n = 16), respectively. Seizure-control rates were stable during patients' use of the extended-release formulation. None of the study patients experienced a treatment-related adverse event. CONCLUSIONS: The total daily dose for patients taking the delayed-formulation may need to be increased by < or = 20% when they are switched to the extended-release formulation. When switching from sprinkles to the extended-release formulation, individual variability must be considered. In patients who have VPA levels near the very high end of the therapeutic range (>100 microg/ml), it may be more prudent to make only minor modifications to the total daily dose during conversion and then to individualize the DVP extended-release dose based on plasma levels.

Adolescent↗