Biomedical subjects
S Knowles
Publications and source records attributed to S Knowles.
Cranial reossification with absorbable plates.
The purpose of this study was to examine the effect of Lactosorb absorbable plates on bone healing across cranial bone defects in the rabbit skull. Two 10-mm diameter parietal skull defects were created in each of 20 rabbits, with one defect being placed on either side of the sagittal suture. In 10 rabbits, an absorbable plate was placed across both the inner and outer cortices of the left defect, and in the other 10 rabbits, an absorbable plate was placed across the outer cortex only of the left defect. The right defect always served as the control side, with no plate being placed across it. Rabbits were killed an average of 25 weeks postoperatively. Areas of reossification in the experimental and control defects of each rabbit were then measured, examined histologically, and compared. Growth across defects spanned by one plate was also compared with growth across defects spanned by two plates. Histologic and statistical analyses revealed no significant differences in reossification between the control and experimental defects in each animal and between the defects spanned by one versus two plates. This study suggests that these copolymer absorbable plates neither inhibit nor facilitate reossification across 10-mm diameter rabbit cranial defects.
Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of 'sulfa' allergy.
Celecoxib, a selective cyclo-oxygenase-2 inhibitor, is a diaryl-substituted pyrazole derivative containing a sulfonamide substituent. Because of this structural component, celecoxib is contraindicated for use in patients who have demonstrated allergic reactions to sulfonamides. However, there is a lack of data demonstrating cross-reactivity among sulfonamide medications. A sulfonamide is any compound with an SO2NH2 moiety. The major difference between sulfonamide antimicrobials and other sulfonamide-containing medications such as furosemide, thiazide diuretics and celecoxib, is that sulfonamide antimicrobials contain an aromatic amine group at the N4 position. This allows for division of the sulfonamides into 2 groups: aromatic amines (i.e., sulfonamide antimicrobials) and nonaromatic amines. In addition, sulfonamide antimicrobials contain a substituted ring at the N1-position; this group is not found with nonaromatic amine-containing sulfonamides. Adverse reactions to sulfonamide antimicrobials include type I, or immunoglobulin (Ig) E-mediated reactions, hypersensitivity syndrome reactions, and severe skin reactions such as toxic epidermal necrolysis. The aromatic amine portion of the sulfonamide antimicrobial is considered to be critical in the development of latter 2 reactions. In susceptible individuals, the hydroxylamine metabolite is unable to be detoxified leading to a cascade of cytotoxic and immunological events that eventually results in the adverse reaction. Since celecoxib does not contain the aromatic amine, adverse reactions such as hypersensitivity syndrome reactions and toxic epidermal necrolysis would not be expected to occur at the same frequency as they do with sulfonamide antimicrobials. Similarly, for IgE-mediated reactions, the N1-substituent and not the sulphonamide moiety is important in determining specificity to antibodies. Celecoxib and other nonaromatic amine-containing sulfonamide medications do not contain the N1-substituent. Cross-reactivity among the various sulfonamide-containing medications has also not been substantiated by published case reports. In fact, conflicting information exists in the literature. Reports showing lack of cross-reactivity balance the few case reports suggesting cross-reactivity. Cross-reactivity between sulfonamide medications should be based on scientific data, including chemistry, metabolism, immune responses and clinical data. Based on the current information, there is no documentation for cross-reactivity between sulfonamide antimicrobials and other sulfonamide medications, such as celecoxib.
Two novel alphaherpesviruses associated with fatal disseminated infections in Atlantic bottlenose dolphins.
Two immature female bottlenose dolphins (Tursiops truncatus) were found stranded on the Atlantic coast of the USA. Necropsy and histopathologic examination of both dolphins demonstrated acute necrotizing lesions in multiple organ systems. Commonly seen in these lesions were cells with enlarged nuclei that contained single 4 to 6 microm diameter homogeneous eosinophilic inclusion bodies that were often surrounded by a clear halo. Ultrastructural examination revealed that intranuclear inclusions contained 90 to 110 nm diameter viral particles with electron-dense cores and hexagonal profiles. Viral particles were also present in the cytoplasm, and these were surrounded by variably electron-dense envelopes. Enveloped virions were 140 nm in diameter. Polymerase chain reactions targeting the DNA polymerase and terminase genes of herpesviruses were carried out on unfixed tissues of both animals, and analysis of the DNA products indicated the presence of two novel alphaherpesviruses. The gross, histologic, ultrastructural, and molecular genetic findings indicate disseminated herpesviral infections, and support the conclusion that the alphaherpesviruses caused the deaths of the two dolphins. This is the first report of disseminated herpesviral infection in cetaceans.
Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.
Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.
An outbreak of multiply resistant Serratia marcescens: the importance of persistent carriage.
An outbreak of multi-resistant Serratia marcescens involving 24 patients occurred in a bone marrow transplant and oncology unit, from September 1998 to June 1999, of whom 14 developed serious infection. This is the first such outbreak described in a BMT unit. All isolates demonstrated the same antimicrobial susceptibility pattern and were the same unusual serotype O21:K14. The antimicrobial susceptibility profile showed reduced susceptibility to ciprofloxacin, gentamicin and piperacillin-tazobactam. As the latter two antimicrobials are part of our empiric therapy for febrile neutropenia, they were substituted with meropenem and amikacin during the outbreak. Investigation revealed breaches in infection control practices. Subsequently, the outbreak was contained following implementation of strict infection control measures. A prominent feature of the outbreak was prolonged carriage in some patients. These patients may have acted as reservoirs for cross-infection. This report also indicates that patients who become colonised with Serratia marcescens may subsequently develop invasive infection during neutropenic periods.
The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus.
Interferon (IFN)-induced antiviral responses are mediated through a variety of proteins, including the double-stranded RNA-dependent protein kinase PKR. Here we show that fibroblasts derived from PKR(-/-) mice are more permissive for vesicular stomatitis virus (VSV) infection than are wild-type fibroblasts and demonstrate a deficiency in alpha/beta-IFN-mediated protection. We further show that mice lacking PKR are extremely susceptible to intranasal VSV infection, succumbing within days after instillation with as few as 50 infectious viral particles. Again, alpha/beta-IFN was unable to rescue PKR(-/-) mice from VSV infection. Surprisingly, intranasally infected PKR(-/-) mice died not from pathology of the central nervous system but rather from acute infection of the respiratory tract, demonstrating high virus titers in the lungs compared to similarly infected wild-type animals. These results confirm the role of PKR as the major component of IFN-mediated resistance to VSV infection. Since previous reports have shown PKR to be nonessential for survival in animals challenged with encephalomyocarditis virus, influenza virus, and vaccinia virus (N. Abraham et al., J. Biol. Chem. 274:5953-5962, 1999; Y. Yang et al., EMBO J. 14:6095-6106, 1995), our findings serve to highlight the premise that host dependence on the various mediators of IFN-induced antiviral defenses is pathogen specific.
Retrospective study on red cell usage in primary total knee replacement surgery.
BACKGROUND AND OBJECTIVES: There is wide variation in the use of red cell transfusions for the same clinical indication. The purpose of the study was to comment on preoperative and discharge haemoglobin (Hb) levels and perioperative blood loss, and to project the Hb level if transfusions were not administered. MATERIALS AND METHODS: The case notes of 187 patients who underwent primary total knee replacement were reviewed retrospectively. RESULTS: More than 90% of the transfusions were given in the immediate postoperative period as a matter of routine and a significant number of transfusions appeared to be unnecessary. CONCLUSION: For surgical procedures involving moderate blood loss, transfusions should not be given as a routine and the decision to transfuse should take into consideration the clinical state of the patient, blood loss and pre- and postoperative Hb levels.
Addendum for guidelines for blood grouping and red cell antibody testing during pregnancy. BCSH Transfusion Task Force.
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p53 protein overexpression and gene mutation in mixed Müllerian tumors of the uterus.
Alteration of the p53 tumor suppressor gene is associated with poor prognosis in many human cancer types. We examined the incidence and prognostic significance of p53 gene alterations in a series of uterine malignant mixed Müllerian tumors (MMT). Nuclear overexpression of p53 protein detected by immunohistochemistry (IHC) with the DO-7 antibody was observed in 12 of 24 (50%) tumors. Mutation of the p53 gene detected by single-strand conformation polymorphism (SSCP) of exons 5 to 8 was found in 11 of 24 (46%) tumors. The incidence of p53 alteration in uterine MMT was significantly higher than in several common epithelial tumor cell types previously investigated in our laboratory using identical techniques. However, unlike these tumors alteration of the p53 gene does not appear to be of prognostic importance in uterine MMT.
p53 protein overexpression is a prognostic indicator of poor survival in stage I endometrial carcinoma.
The prognostic value of p53 protein overexpression was investigated in a large series of early stage endometrial carcinomas with long follow-up (n=179, median follow-up 147 months). P53 overexpression was detected in 10 cases (5.6%). At the end of the study period, 30% (3/10) of patients with p53 protein overexpression had died of their disease compared to 6.5% (11/169) of those without overexpression. Multivariate analysis revealed that only myometrial invasion (RR 2. 1; 95% CI=1.2-3.6; P=0.001) and p53 overexpression (RR 9.5; 95% CI=2. 5-36.8; P=0.007) were independent predictors of survival. These results suggest that immunohistochemical evaluation of p53 protein overexpression provides strong prognostic information for the outcome of endometrial carcinoma patients with early stage disease.
Prenatal diagnosis of hepatic mesenchymal hamartoma.
A case of hepatic mesenchymal hamartoma diagnosed prenatally with ultrasound and confirmed histologically post-delivery is presented. Although histologically benign, this lesion resulted in fetal demise secondary to congestive cardiac failure in the third trimester. The development of non-immune hydrops in association with a fetal hepatic mesenchymal hamartoma is a poor prognostic sign for perinatal survival.
Siblings with a syndrome of hydrocephalus with patent aqueduct, growth retardation and associated anomalies.
We report on male siblings with hydrocephalus with associated abnormalities including growth retardation, midline cleft palate and bilateral 'fisting' of the hands, providing evidence for a familial syndrome of hydrocephalus and associated anomalies.
Drug eruptions in children.
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Skin reactions associated with bisphosphonates: a report of 3 cases and an approach to management.
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The spectrum of cutaneous reactions associated with diltiazem: three cases and a review of the literature.
BACKGROUND: Cutaneous reactions ranging from exanthems to severe adverse events have been reported in association with calcium channel blockers. OBJECTIVE: Our purpose was to document cutaneous eruptions resulting from use of diltiazem. METHODS: We describe three patients who experienced a cutaneous reaction (i.e., hypersensitivity syndrome reaction, pruritic exanthematous eruption, and acute generalized exanthematous pustulosis) possibly induced by diltiazem, summarize adverse reaction reports obtained from the Health Protection Branch, and review the literature on calcium channel blockers inducing cutaneous reactions. RESULTS: Of the 315 cases of possible diltiazem-induced adverse reactions that were reported to the Health Protection Branch, 151 (48%) were cutaneous. The number of diltiazem-induced cutaneous events was significantly greater than those induced by either nifedipine or verapamil. However, no difference was found in the proportion of serious cutaneous adverse events to either of the three drugs. CONCLUSION: Diltiazem has been associated with a variety of cutaneous reactions that appear to occur more frequently than with other calcium channel blockers.
A unique lethal spondylocostal metaphyseal dysplasia: a case report.
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Serum sickness-like reaction to itraconazole.
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