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How many cardiac cycles must be measured to permit accurate RR, QT, and QTc estimates in conscious dogs?

INTRODUCTION: Electrocardiography is an essential tool to assess the liability of test articles to produce torsade de pointes. The number of cardiac cycles that must be measured from a dog to accurately characterize the relationship between RR and QT intervals, and thus assess this liability, is unknown. METHODS: In this study, electrocardiograms (ECGs) were obtained from 12 conscious dogs with sinus rhythm. In each dog, RR and QT intervals were measured for 12 cardiac cycles. Measurements for each were then averaged over all 12 cycles, and those results compared to the average of both the initial 6 and 3 cycles, as well as to the middle cycle alone, for 12, 6, and 4 of the dogs. QTc was calculated by dividing each QT by the cube root of the preceding RR interval. RESULTS: We found no significant differences in the results of measurements of RR, QT, or QTc obtained from 12, 6, 3, or 1 cycle, whether from 12, 6, or 4 dogs. Intraobserver variability of ECG measurements was tested by having a single observer measure 10 copies of 12 different ECGs. The greatest coefficient of variation (S.D./mean) for the measurement of any ECG parameter was less than 2.5%. DISCUSSION: We conclude that measurements of RR and QT intervals made by a trained observer from 1 cardiac cycle accurately reflect those that are averaged from 3, 6, or 12 cycles whether the number of dogs per group is 12, 6, or 4.

Animals↗

PPV long-distance movement is occasionally permitted in resistant apricot hosts.

The interactions between Plum pox virus (PPV), a member of the Potyvirus genus, and Prunus host plants are, up to now, poorly understood. In the current paper, fluorescence stereomicroscopy, in situ hybridisation and immunogold detection were performed in order to evaluate the virus transport and cellular distribution. The behavior of PPV in several susceptible (cv. "Moniqui" and "Screara") and resistant apricot genotypes (cv. "Harlayne", "Henderson", "Harcot", "Goldrich", "Stella" and "Stark Early Orange") were compared. Viral RNA was detected by in situ hybridisation in stem tissues close to the inoculation point, irrespective of the resistance status of the variety. Systemic infection was evidenced by virus immunodetection and by fluorescence detection of a GFP-tagged PPV in distant leaf sections. The signal obtained by in situ hybridisation colocalised with the fluorescence produced by GFP-tagged PPV in the same plant material but did not colocalise with the signal obtained by immunostaining. Intensity of the PPV infection in susceptible apricot cultivars varied depending on genotypes. The behavior of PPV in systemic leaves was clearly distinct between susceptible and resistant cultivars. While PPV was spreading widely around the major and minor veins in susceptible leaves, in the resistant apricot genotypes it was restricted to isolated spots consisting of few cells embedded in the mesophyll tissue. In summary, differences in the ability of PPV to systemically infect susceptible and resistant apricot cultivars were evident but nevertheless, long-distance transport of PPV occured in resistant apricot scions.

Disease Susceptibility↗

The Oikopleura coenocyst, a unique chordate germ cell permitting rapid, extensive modulation of oocyte production.

The ability to adjust reproductive output to environmental conditions is important to the fitness of a species. The semelparous, chordate, Oikopleura dioica, is particularly adept in producing a highly variable number of oocytes in its short life cycle. Here we show that this entails an original reproductive strategy in which the entire female germline is contained in a single multinucleate cell, the "coenocyst". After an initial phase of syncytial nuclear proliferation half of the nuclei entered meiosis whereas the other half became highly polyploid. The inner F-actin network, with associated plasma membranes, formed a highly ramified infrastructure in which each meiotic nucleus was contained in a pseudo-compartmentalized pro-oocyte linked to the common cytoplasm via ring canals. At a set developmental time, a subset of the pro-oocytes was selected for synchronous growth and the common coenocyst cytoplasm was equally partitioned by transfer through the ring canals. Examination of related species indicated that the coenocyst arrangement is a conserved feature of Appendicularian oogenesis allowing efficient numerical adjustment of oocyte production. As Appendicularia are the second most abundant class of zooplankton, with a world-wide distribution, the coenocyst is clearly a common and successful reproductive strategy on a global scale.

Actins↗

Ablating CAR and integrin binding in adenovirus vectors reduces nontarget organ transduction and permits sustained bloodstream persistence following intraperitoneal administration.

To create tumor-targeted Ad vectors, ablation of native CAR and integrin receptor binding is crucial to enhance the specificity of tumor transduction. Toward this aim, we have previously created base vectors in which binding to CAR (single-ablated) or to both CAR and integrins (double-ablated) has been ablated. In this study, the biodistribution of the conventional (CAR and integrin binding intact), single-ablated, and double-ablated vectors was evaluated following intraperitoneal administration. The mesothelial lining of the peritoneal organs was the principle site of CAR-dependent gene transfer by the conventional vector. Surprisingly, the single-ablated vector strongly transduced the liver parenchyma rather than the mesothelium, while the double-ablated vector did not significantly transduce the parenchyma or mesothelium. The high level of parenchymal transduction by the single-ablated vector suggested that it efficiently entered the bloodstream from the peritoneal cavity. Consistent with this hypothesis, a large proportion of active particles distributed and persisted in the bloodstream following intraperitoneal administration of either the single- or the double-ablated vector. The above results suggest that the double-ablated vector backbone may not only significantly improve targeting to cancers located in the peritoneal cavity, but may also significantly improve targeting to metastatic tumors located throughout the body by virtue of its enhanced bloodstream persistence.

Adenoviridae↗

Modification of the diagnostic criteria proposed by the Duke Endocarditis Service to permit improved diagnosis of Q fever endocarditis.

BACKGROUND: Q fever endocarditis is a life-threatening disease for which the diagnosis is usually based on serology. The major microbiologic criterion for the diagnosis of infectious endocarditis (two separate positive blood cultures) cannot be achieved in most routine laboratories because of the biohazard associated with the culture of Coxiella burnetii, the etiological agent of Q fever. PURPOSE: Recently, new criteria for the diagnosis of infectious endocarditis have been proposed, and in this study we attempted to assess the suitability of these criteria specifically for the diagnosis of Q fever endocarditis. PATIENTS AND METHODS: To achieve this aim, we first selected from our series 20 recent cases in whom endocarditis had been confirmed following valvular pathological examination, and for whom microbiological evidence for the involvement of C burnetii was available. Then, we applied the criteria proposed by the Duke Endocarditis Service (ie, C burnetii positive serology being considered a minor criterion) to this cohort of patients but excluding pathological findings. Although the Duke Endocarditis Service criteria confirmed diagnosis in 16 of the patients, 4 were misclassified as "possible" cases (20%). However, when the Q fever serological results (using an 1/800 antiphase I immunoglobulin G cut off) and single blood culture results were changed from minor to major diagnostic criteria, endocarditis was confirmed in them all. A second time, prospectively, we applied the Duke Endocarditis Service criteria to a further 5 patients affected with Q fever endocarditis. Strict application of these criteria resulted in 1 of the 5 being misdiagnosed. Applying the suggested modification for C burnetii results, all 5 were confirmed as having infectious endocarditis. CONCLUSION: We propose that the modifications discussed in this study be applied to the Duke Endocarditis Service criteria in order that the diagnosis of C burnetii induced endocarditis is improved.

Coxiella burnetii↗

Superficial laser vulvectomy. II. The anatomic and biophysical principles permitting accurate control over the depth of dermal destruction with the carbon dioxide laser.

The rationale for using the carbon dioxide laser to treat either vulvar intraepithelial neoplasia or extensive papillomaviral infections is to destroy the entire area of abnormal epithelium to a shallow depth, so that rapid healing will occur from normal keratinocytes in the underlying pilosebaceous glands. After the first laser impact, anatomic landmarks in the crater base are disguised by a layer of charred proteins, and any structure that is visible will already have suffered thermal necrosis. Accurate control of depth depends upon special surgical strategies that correlate the level of the underlying zone of thermal necrosis with specific visual appearances within the zone of vaporization. Maneuvers that limit depth of penetration to one of three desirable surgical planes (basement membrane, papillary dermis, midreticular dermis) are described.

Animals↗

New technologies permit safe abortion at less than six weeks' gestation and provide timely detection of ectopic gestation.

OBJECTIVE: The previously held dictum that elective abortion before 6 weeks' gestation carried greater risks than a later procedure was challenged by this protocol. STUDY DESIGN: This study evaluated a protocol for abortion before the customary 6 weeks' gestation. Patients willing to return to the clinic within 72 hours were given the option of elective abortion even when no gestational sac could be visualized with transvaginal ultrasonography. When no chorionic membrane with villi was seen in the curettings, postoperative serum levels of beta-human chorionic gonadotropin confirmed complete evacuation or diagnosed ectopic pregnancy. RESULTS: In 1530 abortion procedures at < 6 weeks' gestation by ultrasonographic criteria no serious complications occurred. In addition, 9 (0.67%) unsuspected ectopic pregnancies were diagnosed. CONCLUSIONS: Abortion before 6 weeks' gestation is safe, given close surveillance. Early termination combined with vaginal ultrasonography and follow-up with beta-human chorionic gonadotropin measurements allows diagnosis of early, unsuspected ectopic pregnancy. Ectopic pregnancy was found to be uncommon in women requesting early abortion.

Abortion, Induced↗

A learning prescription permits feedback on feedback.

BACKGROUND: Students consistently identified inadequate feedback as a deficiency in our third-year clerkship. METHODS: We asked students to solicit one faculty and one resident every 2 weeks for written feedback on a "feedback prescription pad." Each prescription requested four comments: two things the student did well and two things the student needs to improve. Students rated feedback using a five-point scale. A three-point categorization scheme was employed to assess the quality of feedback. RESULTS: Students' rating of feedback improved significantly compared with a previous time period (3.5 +/- 1.2 versus 2.6 +/- 1.2, P <0.01). Interrater reliability of our categorization scheme was high (kappa > or =0.75, P <0.01) and demonstrated that only 10% of comments were specific enough to qualify as effective feedback. CONCLUSIONS: Feedback prescription pads were a simple method to facilitate feedback. Although students appreciated feedback, most feedback was inadequate. Faculty development programs to enhance student feedback should be a priority of clinical medical education.

Clinical Clerkship↗

Successful treatment of ongoing intestinal allograft rejection permits recovery of graft structure and function.

Acute rejection episodes often complicate clinical small bowel transplantation, which prompted us to investigate whether such episodes can be reversed and the intestinal graft salvaged. Inbred Lewis rats that received fully allogeneic Brown-Norway small bowel allografts were treated with cyclosporin A (10 mg/kg) for 5 days, and the drug was then discontinued. Clinical and histologic signs of acute rejection developed, and the animals were subsequently treated with FK 506 (2 mg/kg) on days 14, 16, and 18. Survival was significantly prolonged (201.7 +/- 46.8 days) when compared with animals that were not administered FK 506 (16.5 +/- 0.8 days) or allograft recipients that received no immunosuppressive therapy (10.8 +/- 0.7 days). The histologic changes and functional impairment due to rejection that were observed prior to the start of the FK 506-therapy were reversed. However, biopsy specimens of all animals exhibited features of chronic rejection. This study provides evidence that acute rejection of intestinal allografts can be successfully treated with a short course of FK 506.

Acute Disease↗

Constituent analysis may permit improved diagnosis of intra-abdominal abscess.

BACKGROUND: Intra-abdominal abscesses (IAA) often fail to resolve with intravenous antibiotics alone and frequently require drainage. Diagnosis of IAA in postoperative patients with other likely sources of infection is very difficult. PATIENTS AND METHODS: In order to characterize IAA and identify parameters that might facilitate diagnosis, we prospectively examined peripheral blood and pus of 15 consecutive patients with IAA and compared them to samples from 34 consecutive patients with soft-tissue abscesses (STA). RESULTS: Serum interleukin (IL)-10 was elevated in IAA patients, while abnormally detectable serum IL-4 was demonstrated in the pus of both IAA and STA patients. IL-10 in IAA pus was more than 11-fold higher than in STA, whereas IL-4 in pus was similar in both types of abscesses. Both IL-4 and IL-10 were 4- to 10-fold higher in IAA and STA pus than in corresponding patient serum. Serum lysozyme was, however, significantly elevated in all abscess patients. CONCLUSIONS: The presence of IL-4 and IL-10 may indicate a T-helper 2 lymphocyte response in the etiology of abscess formation and persistence, although precise determination of T-helper 1-related cytokines is needed to verify this. Serum lysozyme and IL-10 may be reliable and relatively inexpensive diagnostic aids.

Abdominal Abscess↗

Massive pulmonary embolism permitting paradoxical systemic arterial embolism: successful surgical management.

The case of a young woman, receiving oral contraceptives, who developed massive pulmonary embolism producing circulatory collapse and paradoxical arterial embolism through a patent foramen ovale is documented.. Limb viability was threatened. Emergency management included removal of arterial and pulmonary emboli, surgical closure of the patent foramen ovale, inferior caval partitioning, ovarian vein ligation, and short-term anticoagulation. Recovery was rapid and complete.

Adult↗

Synthesis of a new photoreactive C5a analog that permits identification of the ligand binding component of the granulocyte C5a receptor.

Human C5a is a complement derived inflammatory mediator that binds to specific receptors that are found in the granulocyte plasma membrane. A new photoreactive C5a analog, that can be radiolabeled in the aryl azide moiety, has been synthesized by coupling p-azidosalicyl-2-mercapto-N-ethylamide-2'-thiopyridine disulfide to a partially reduced form of C5a. This unique analog (ASAMEA-SC5a) specifically bound to the granulocyte C5a receptor with an apparent Kd of 1.8 nM, a value that is comparable to that of the native ligand. Photoactivation resulted in crosslinking of this probe to the granulocyte C5a receptor. Subsequent reductions of the complex produced a radiolabeled C5a receptor, or a subunit of this receptor that had an apparent molecular weight of 47,000 Daltons on SDS-PAGE.

Affinity Labels↗

Site-specific DNA hypomethylation permits expression of the IRBP gene.

Interphotoreceptor retinoid binding protein (IRBP), a putative component of the visual cycle, is expressed selectively in the retina and pineal gland. This study examined whether site-specific DNA hypomethylation plays a role in this expression regulation. Southern blotting of HpaII and MspI digests of DNA from various bovine and murine tissues (whole brain, retina, pineal gland, superior colliculus, cortex, thymus, habenular nucleus, cornea, liver, tail, and kidney) revealed that specific CpG dinucleotides in the IRBP gene promoter are hypomethylated in DNA from retinal photoreceptor cells and pineal gland compared to DNA from other tissues. These sites are methylated in DNA from non-photoreceptor retinal cells. Exogenous methylation of these sites diminished DNA:protein binding in electrophoretic mobility shift assays. HpaII methylation of chloramphenicol acetyltransferase reporter constructs suppressed IRBP but not SV40 promoter activity in transiently transfected primary cultures of embryonic chick retinal cells. These data indicate that specific cytosines in the bovine and murine IRBP promoters are unmethylated in photoreceptive cells but methylated in other tissues. This differential DNA methylation may modulate IRBP gene expression since exogenous methylation of the murine sites suppresses reporter gene transcription, apparently by inhibiting DNA:protein binding events.

Animals↗