Correction: Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Clinical impact of positive Propionibacterium acnes cultures in orthopedic surgery.

BACKGROUND: The clinical significance of a positive culture to Propionibacterium acnes in orthopedic specimens remains unclear, whether about its role as a contaminant or a pathogen, or its impact as a coinfectant. Therefore, we performed a retrospective study to provide a more accurate description of the clinical impact of P. acnes in an orthopedic population aiming to determine: 1) if there is a clinical difference between P. acnes infection and contamination? 2) If there is a clinical difference between P. acnes monoinfection, and coinfection. HYPOTHESIS: There is a clinical difference between P. acnes infection and contamination. MATERIALS AND METHODS: Patients were selected over a five-year period, and those with a minimum of one positive culture for P. acnes, from any intraoperative orthopedic tissue sample, were included in the study. P. acnes infection was defined as the isolation of P. acnes from≥2 specimens, or in only one specimen, in the presence of typical perioperative findings and/or local signs of infection. RESULTS: A total of 68 patients had a positive P. acnes culture, 35 of which were considered to be infected. The infections affected mostly males (29/35-83%), occurred mostly in shoulders (22/35-63%), and at a site already containing an orthopedic implant (32/35-91%). Local inflammatory signs were present in half of the cases when an infection was diagnosed. Coinfection with other pathogens was present in 31% of patients (11/35). When comparing patients coinfected with P. acnes, and those who were monoinfected, the latter presented less often with local inflammatory signs. Recurrence rate was 24% (8/35) and the only risk factor for recurrence was the presence of a monoinfection. DISCUSSION: This study confirms the pathogenicity of P. acnes in an orthopedic population, as it is present in multiple samples in the same patient, and because it is present in cultures from cases with clinical recurrence. Our study showed that monoinfections differ from coinfections mainly by their higher risk of recurrence. LEVEL OF EVIDENCE: Level IV retrospective case series.

Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients.

Imatinib mesylate (IM) therapy has been shown to induce lower T cell counts in chronic myelogenous leukemia (CML) patients and an interference of IM with T cell receptor (TCR) signaling has been invoked to explain this observation. However, IL-7 and TCR signaling are both essential for lymphocyte survival. This study was undertaken to determine whether IM interferes with IL-7 or TCR signaling to explain lower T cell counts in patients. At diagnosis, CML patients have typically lower CD4+ counts in their blood, yet CD8+ counts are normal or even increased in some. Following the initiation of IM treatment, CD4+ counts were further diminished and CD8+ T lymphocytes were dramatically decreased. In vitro studies confirmed IM interference with TCR signaling through the inhibition of ERK phosphorylation and we showed a similar effect on IL-7 signaling and STAT5 phosphorylation (STAT5-p). Importantly however, using an in vivo mouse model, we demonstrated that IM impaired T cell survival through the inhibition of IL-7 and STAT5-p but not TCR signaling which remained unaffected during IM therapy. Thus, off-target inhibitory effects of IM on IL-7 and STAT5-p explain how T cell lymphopenia occurs in patients treated with IM.

The expanding universe of alkaloid biosynthesis.

Characterization of many of the major gene families responsible for the generation of central intermediates and for their decoration, together with the development of large genomics and proteomics databases, has revolutionized our capability to identify exotic and interesting natural-product pathways. Over the next few years, these tools will facilitate dramatic advances in our knowledge of the biosynthesis of alkaloids, which will far surpass that which we have learned in the past 50 years. These tools will also be exploited for the rapid characterization of regulatory genes, which control the development of specialized cell factories for alkaloid biosynthesis.

Dysthyroid optic neuropathy. Clinical profile and rationale for management.

Dysthyroid optic neuropathy (DON) was diagnosed in 36 eyes of 21 patients with progressive visual loss and congestive ophthalmopathy. Systemic features in the patients with DON did not differ from those reported for Graves' disease patients except that patients with DON were older (mean age, 61 years) and did not show female preponderance. Congestive symptoms always preceded visual loss, which was gradual in onset and bilateral in most patients but acute and asymmetrical in several. Presenting acuities were poorer than 20/60 in 50% of cases; central scotomas, sometimes combined with inferior depression, were the predominant field defects. Congestive signs were of moderate intensity without severe proptosis or exposure keratopathy. Bilateral and symmetrical ductional restriction was the most common motility disturbance. Oral corticosteroids were effective in restoring visual function in ten of 21 eyes treated. Many steroid-unresponsive eyes were improved promptly by supervoltage orbital irradiation or surgical decompression. In general, therapeutic intervention appeared to hasten recovery and improve visual outcome.

Effect of occlusive pressure patching on the rate of epithelial wound healing after photorefractive keratectomy.

PURPOSE: This study measured the effect of pressure patching on the rate of epithelial wound healing in 41 myopic patients after photorefractive keratectomy (PRK). METHODS: On day 0, mechanical debridement was done to remove the central 6.5 mm diameter of epithelium. Subsequently, a 5.0 mm diameter photoablation was performed, the depth of ablation being proportional to the degree of myopia (-1.0 to -6.0 diopters). The patients were discharged with an application of antibiotic/steroid ointment (A/S) followed by pressure patching. On day 1, the epithelial defects were stained with fluorescein and photographed. The patients were then randomized prospectively into two groups: Group 1 was pressure patched after application of A/S ointment; Group 2 received A/S ointment twice a day without patching. A photograph of the remaining epithelial defect was taken on day 2. The area of the epithelial defect was measured with a computerized image analyzer. Wound diameter (radius) was used to calculate the epithelial healing rate (EHR). RESULTS: Between days 1 and 2, the mean EHR in Group 1 was 0.072 +/- 0.005 mm/hr and in Group 2, 0.056 +/- 0.004 mm/hr (P < 0.05). There was no correlation between the EHR and patient gender or the degree of myopia. However, a correlation was noted between patient age and wound size on day 1. CONCLUSION: Pressure patching significantly accelerated the EHR following PRK.

[Hockey injuries: consultations in a hospital center in Quebec]. / Blessures liées à la pratique du hockey: consultations dans un centre hospitalier de la région de Québec.

OBJECTIVES: Assess the context and characteristics of hockey injuries, and evaluate the probable effects of regulations concerning mandatory use of head and neck protective equipment. DESIGN: Descriptive study of 247 patients suffering from hockey injuries. Cases were recorded at the emergency room of the Hôpital de l'Enfant-Jésus, in Quebec City, from October 1 1991 to April 30 1992. Injury characteristics are presented by categories, and "Organized hockey on skates" (HPO) is the only category where protective equipment is mandatory. RESULTS: Nearly 42% of consultations were related to non-HPO. In the HPO injuries 15.4% were head injuries whereas in other categories, head injuries represented 31.4%, 33.3% and 44.0% of total injuries. DISCUSSION: Data suggest that regulation imposing mandatory head and neck protection should be maintained in the HPO category because of its apparent preventive effect. Accordingly, implementation could also be considered in other categories.

Bonnet-Dechaume-Blanc syndrome.

A 16 year old girl presenting the visual disturbances was found to have a right retinal arteriovenous communication. The provisional diagnosis of Bonnet-Dechaume-Blanc syndrome was confirmed by angiographic demonstration of ipsilateral orbital and intracranital arteriovenous malformations.

Glucose tolerance and lipid profiles in dogs fed different fiber diets.

Increased dietary fiber is thought to have beneficial effects on health in humans. In diabetic dogs, a beneficial effect of fiber on glycemia has been suggested, while its effect on lipid profiles in dogs has not been described. The effects of different amounts and types of fiber on glucose tolerance and lipid concentrations were evaluated and compared with those of a standard maintenance ration in 30 healthy dogs. It was concluded that increased fiber intake had no influence on glucose in healthy dogs but it may have modulated lipid homeostasis.

Securing the data economy: translating privacy and enacting security in the development of DataSHIELD.

Contemporary bioscience is seeing the emergence of a new data economy: with data as its fundamental unit of exchange. While sharing data within this new 'economy' provides many potential advantages, the sharing of individual data raises important social and ethical concerns. We examine ongoing development of one technology, DataSHIELD, which appears to elide privacy concerns about sharing data by enabling shared analysis while not actually sharing any individual-level data. We combine presentation of the development of DataSHIELD with presentation of an ethnographic study of a workshop to test the technology. DataSHIELD produced an application of the norm of privacy that was practical, flexible and operationalizable in researchers' everyday activities, and one which fulfilled the requirements of ethics committees. We demonstrated that an analysis run via DataSHIELD could precisely replicate results produced by a standard analysis where all data are physically pooled and analyzed together. In developing DataSHIELD, the ethical concept of privacy was transformed into an issue of security. Development of DataSHIELD was based on social practices as well as scientific and ethical motivations. Therefore, the 'success' of DataSHIELD would, likewise, be dependent on more than just the mathematics and the security of the technology.

Molecular and biochemical analysis of a Madagascar periwinkle root-specific minovincinine-19-hydroxy-O-acetyltransferase.

The terminal steps in the biosynthesis of the monoterpenoid indole alkaloids vindoline and minovincinine are catalyzed by separate acetyl coenzyme A-dependent O-acetyltransferases in Madagascar periwinkle (Catharanthus roseus G. Don). Two genes were isolated that had 63% nucleic acid identity and whose deduced amino acid sequences were 78% identical. Active enzymes that were expressed as recombinant His-tagged proteins in Escherichia coli were named minovincinine-19-O-acetyltransferase (MAT) and deacetylvindoline-4-O-acetyltransferase (DAT) because they catalyzed the 19-O-acetylation of indole alkaloids such as minovincinine and hörhammericine and the 4-O-acetylation of deacetylvindoline, respectively. Kinetic studies showed that the catalytic efficiency of recombinant MAT (rMAT) was very poor compared with that of recombinant DAT (rDAT), whose turnover rates for Acetyl-coenzyme A and deacetylvindoline were approximately 240- and 10,000-fold greater than those of rMAT. Northern-blot analyses showed that MAT is expressed in cortical cells of the root tip, whereas DAT is only expressed in specialized idioblast and laticifer cells within light exposed tissues like leaves and stems. The coincident expression of trytophan decarboxylase, strictosidine synthase, and MAT within root cortical cells suggests that the entire pathway for the biosynthesis of tabersonine and its substituted analogs occurs within these cells. The ability of MAT to catalyze the 4-O-acetylation of deacetylvindoline with low efficiency suggests that this enzyme, rather than DAT, is involved in vindoline biosynthesis within transformed cell and root cultures, which accumulate low levels of this alkaloid under certain circumstances.

Passive and active inspired gas humidification in infants and children.

The hypothesis that both active and passive airway humidification prevents hypothermia in infants and children, but that neither decreases the duration of postoperative recovery was tested. Twenty-seven ASA physical status 1 or 2 patients were studied who weighed between 5 and 30 kg, underwent superficial operations, were anesthetized with halothane and 70% N2O, and whose lungs were ventilated via a Rees modification of an Ayre's t-piece. The children were randomly assigned to receive active airway humidification and warming using an MR450 Servo airway heater and humidifier set at 37 degrees C (n = 10), passive airway humidification using the Humid-Vent 1 heat and moisture exchanger placed between the Ayre's t-piece and the endotracheal tube (n = 8), or no airway humidification and heating (control, n = 9). Distal tracheal and tympanic membrane temperatures and airway humidity were recorded during the first 90 min of surgery. Rectal temperature was measured during the postanesthetic recovery period. Relative humidity of inspired respiratory gases was approximately 30% in the control group and approximately 90% in the group given active airway humidification. Initial inspired humidity in the passive humidification group (50%) increased to approximately 80%, a level not significantly different from that in the active group after 80 min of anesthesia. Central body temperature increased 0.25 degrees C during active active airway humidification and heating, whereas temperature decreased 0.25 degrees C during passive humidification and 0.75 degrees C without airway humidification. Distal tracheal temperature was significantly higher in the groups given passive and active humidification than in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraoperative temperature monitoring sites in infants and children and the effect of inspired gas warming on esophageal temperature.

This study tested the hypotheses that 1) temperatures of "central" sites are similar in infants and children undergoing noncardiac surgery and 2) airway heating and humidification increases distal esophageal temperature. Twenty children were randomly assigned to receive 1) active airway humidification using an airway heater and humidifier set at 37 degrees C (N = 8), 2) passive airway humidification using a heat and moisture exchanger (N = 6), or 3) no airway humidification and/or heating (control, N = 6). There were no statistically significant differences between tympanic membrane, esophageal, rectal, and axillary temperatures. The temperatures of the peripheral skin surface (forearm and fingertip) were significantly lower than tympanic membrane temperature and significantly different from each other. Although esophageal and tympanic membrane temperatures in the entire group were similar, esophageal temperatures in patients receiving active and passive airway humidification were about 0.35 degrees C above tympanic temperatures after induction of anesthesia. In contrast, esophageal temperatures in patients without airway humidification were 0.25 degrees C below tympanic temperatures after induction of anesthesia. Esophageal-tympanic membrane temperature differences in the patients given active and passive humidification differed significantly from the corresponding sum in the control group at all times, but not from each other.

Primary aberrant third nerve regeneration.

The clinical and neuroradiological features in 4 patients with the syndrome of aberrant regeneration of the third nerve are presented. In contrast to what is commonly seen, the syndrome was not preceded by third nerve palsy. A petrous apex-cavernous sinus meningioma was the underlying lesion in all 4 patients. Surgical and pathological confirmation of the diagnosis was obtained in 3. Regardless of whether the other ocular motor nerves are spared (as in our patients) or involved (as in other cases reported in the literature), primary aberrant regeneration of the oculomotor nerve appears to be characteristic of a cavernous sinus meningioma.

The terminal O-acetyltransferase involved in vindoline biosynthesis defines a new class of proteins responsible for coenzyme A-dependent acyl transfer.

The gene encoding acetyl CoA:deacetylvindoline 4-O-acetyltransferase (DAT) (EC 2.3.1.107) which catalyzes the last step in vindoline biosynthesis was isolated and characterized. The genomic clone encoded a 50 kDa polypeptide containing the sequences of nine tryptic fragments derived from the purified DAT heterodimer. However, cleavage of DAT protein to yield a heterodimer appears to be an artifact of the protein purification procedure, since the size of the protein (50 kDa) cross-reacting with anti-DAT antibody in seedlings and in leaves of various ages also corresponds to the size of the active recombinant enzyme. Studies with the intact plant and with developing seedlings showed that induction of DAT mRNA, protein accumulation and enzyme activity occurred preferentially in vindoline producing tissues such as leaves and cotyledons of light-treated etiolated seedlings. The ORF of DAT showed significant sequence identity to 19 other plant genes, whose biochemical functions were mostly unknown. The Mr of approximately 50 kDa, a HXXXDG triad, and a DFGWGKP consensus sequence are highly conserved among the 20 plant genes and these criteria may be useful to identify this type of acyltransferase. The involvement of some of these genes in epicuticular wax biosynthesis, fruit-ripening and in benzoyltransfer reactions indicates that the plant kingdom contains a superfamily of multifunctional acyltransferases which operate by a reaction mechanism related to the ancient chloramphenicol O-acetyltransferase and dihydrolipoyl acetyltransferase class of enzymes.

Modification of the electrostatic environment is tolerated in the oxyanion hole of the cysteine protease papain.

The oxyanion hole in cysteine and serine proteases can be viewed as an arrangement of prealigned dipoles that complements the changes in charge distribution during the enzymatic reaction. Because of the electrostatic nature of the interaction involved in the oxyanion hole, the introduction of charged residues in that region could have a major effect on the catalytic properties of the enzyme. In this study, residue Gln19, which contributes to one of the hydrogen bonds in the oxyanion hole of papain, has been replaced by glutamic acid, histidine, and asparagine residues. These mutations result in 65-315-fold decreases in kcat/KM, supporting our previous finding that the side chain of Gln19 contributes to transition state stabilization in the oxyanion hole of papain (Ménard et al., 1991a). Since papain is active over a wide range of pH values, the influence of side chain ionization on activity could be measured quantitatively with the mutant Gln19Glu. The pH dependency of kcat/KM for Gln19Glu is not of the classical bell-shaped form normally observed for papain, but instead is modulated by ionization of the Glu19 side chain with a pKa of 6.02. The Gln19Glu mutant at low pH, where the Glu19 side chain is neutral, is the enzyme that displays activity closest to that of wild-type enzyme, with a (kcat/KM)1lim value only 20-fold lower than that for papain. As expected, the activity of the Gln19Glu mutant decreases when the Glu19 side chain ionizes. However, introduction of the negatively charged glutamate into the oxyanion hole of papain leads to a further reduction in activity of only 12-fold, and this mutant is still more active than the Gln19Ser enzyme and only 3-fold less active than Gln19Asn.(ABSTRACT TRUNCATED AT 250 WORDS)