Plate failure by bending following tibial fracture stabilisation in 10 cats.

OBJECTIVE: To describe the clinical findings and management of tibial fractures in cats in which osteosynthesis failed due to plate bending. METHODS: Case records and radiographs of cat tibial fracture repairs from five referral centres were reviewed for signalment and to assess incidence of plate failure by bending. Cats that sustained plate bending following plate or plate-rod fixation were reviewed for fracture configuration, repair method, initial postoperative and postfailure tibial alignment, revision treatment and outcome. RESULTS: The incidence of plate bending in cat fractures managed with plate and plate-rod fixation in the four referral centres where the overall number could be established was 13% (8/60). In the 10 cats in which plates bent, initial fractures were generally oblique or spiral with mild comminution and located in the middle or distal third of the tibia. Mean time to implant failure was 24 days (range 2 to 56 days). Mean tibial valgus angle increased from 12·9° to 30·9° following bending of the plate. Short-term outcome following revision surgery using orthogonal plating or stacked medial plates was favourable with improvement in tibial valgus in all five fractures with follow-up data. CLINICAL SIGNIFICANCE: Plate bending following tibial fracture stabilisation in these 10 cats resulted in tibial valgus deformation. Consideration of plate and/or intramedullary rod selection and application should be given to avoid a plate strain environment that exceeds the yield point of the plate.

Assessing torsion of the medial cortex of the canine tibia using computed tomography multiplanar reconstruction.

OBJECTIVES: To describe a protocol for the measurement of tibial rotational alignment using CT multiplanar reconstructions. To establish the feasibility of producing general guidelines for the amount of torsional contouring to apply to a bone plate applied to the medial aspect of the tibia during repair of a non-reducible tibial fracture. METHODS: CT scans of the pelvic limbs of 15 chondrodystrophic and 34 non-chondrodystrophic dogs were studied. Medial tibial cortex torsion angle and distal medial tibial cortex angle were determined from CT multiplanar reconstructions. Medial plate application was simulated using a plate contoured to the group mean medial tibial cortex torsion angle and post-simulation tibial rotational alignment was assessed. RESULTS: Mean medial tibial cortex torsion angles were 23° (chondrodystrophic) and 26° (non-chondrodystrophic). Following simulated plate application the change in medial tibial cortex torsion was less than 10° in 73% of chondrodystrophic and 93% of non-chondrodystrophic tibias. In total, 93% of chondrodystrophic and 97% of non-chondrodystrophic tibias had post-simulation distal medial tibial cortex angle less than 10° from the group mean pre-simulation distal medial tibial cortex angle. CLINICAL SIGNIFICANCE: Medial tibial cortex torsion and tibial rotational alignment can be measured using the protocol described in this study. 26° of internal torsional tibial plate pre-contouring may be appropriate for non-chondrodystrophic dogs, but further clinical validation is required.

Peripheral and central nervous system inhibition of 11ß-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384.

ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-(2)H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1-50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ≥2 mg daily maintained peripheral HSD-1 inhibition ≥88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ≥81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ≥2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

Bilateral medial displacement of the biceps tendon of origin: repair using polypropylene mesh and staples.

A three-year-old male greyhound was presented with acute onset right forelimb lameness because of medial displacement of the biceps tendon of origin. Ultrasonographic examination confirmed the diagnosis, and a concomitant partial tear of the medial glenohumeral ligament was detected during arthroscopy. To stabilise the biceps tendon, polypropylene mesh was fixed across the intertubercular groove to replace the torn transverse humeral retinaculum. Recovery was uneventful and lameness resolved. Fifteen months later, the dog was presented with medial displacement of the biceps tendon of origin of the left shoulder, and was treated successfully using the same technique.

A comparison of pectin, polyphenols, and phytosterols, alone or in combination, to lovastatin for reduction of serum lipids in familial hypercholesterolemic swine.

Greater than 50% of Americans use some form of a dietary supplement, and a diagnosis of coronary artery disease is associated with higher supplement use. The objective of this study was to compare nutritional supplements (pectin, polyphenols, and phytosterols) to lovastatin to reduce serum cholesterol. Familial hypercholesterolemic (FH) swine received the same amount of basal diet (control) in addition to pectin (30 g/day), polyphenols (20 g/day), phytosterols (6 g/day), and all possible combinations in contrast to lovastatin (3 mg/kg of body weight). The experimental design consisted of 4 weeks of basal diet followed by 4 weeks of basal diet plus the supplement treatment. All of the supplements, except pectin, reduced total cholesterol by an average of 71 +/- 19 mg/dL in comparison to the control diet (53 +/- 20 mg/dL) and lovastatin (143 +/- 21 mg/dL) during the 5-8-week treatment period. Serum high-density lipoprotein-cholesterol remained unchanged, while serum triglycerides changed independent of diet. During the 5-8-week treatment period serum low-density lipoprotein (LDL)-cholesterol was reduced maximally 22%, 19%, 20%, 17%, 18%, and 17% by polyphenols, phytosterols, pectin + polyphenols, pectin + phytosterols, polyphenols + phytosterols, and pectin + polyphenols + phytosterols, respectively, compared to control (8%) and lovastatin (40%). Phytosterols was the most effective supplementation, while both phytosterol and polyphenol supplements enhanced the reduction in LDL-cholesterol of pectin-containing diets. Supplements effectively reduced cholesterol in FH swine by half compared to lovastatin. Results suggest that more research on the use of dietary supplements, alone or in combination with statins, to reduce LDL-cholesterol is justified.

The interaction of oestrogen receptor status and pathological features with adjuvant treatment in relation to survival in patients with operable breast cancer: a retrospective study of 2660 patients.

The oestrogen receptor (ER) status of 2660 patients with primary breast cancer has been related to the effect of different adjuvant systemic therapies on survival. However, as patients in the various treatment groups also had different prognostic features comparison between treatments was difficult. Over 90% of patients receiving tamoxifen (Tam) were postmenopausal compared with <20% of those receiving chemotherapy (CT). The latter had more positive nodes (85% vs 54%) and grade III tumours (54% vs 30%) than the Tam group. The combined CT and Tam group had similar characteristics to the CT alone group. The current reported increase in the proportion of women with ER+ tumours is explained by immunohistochemical analysis of ER and screening programmes. ER status was unrelated to survival in patients with small, low grade, node-negative tumours which was no different from that expected for age-matched women taken from the general population. The value of adjuvant treatment in these patients is therefore questionable. In those given any adjuvant treatment, survival of women with ER+ tumours was prolonged, with the greatest effect being seen in those receiving Tam. Patients with ER- tumours benefited from CT but the addition of Tam to CT improved survival only in those with ER+ tumours. ER status is now established as a major predictive factor for treatment selection in primary disease. Studies of prognostic and predictive markers may be invalidated by use of adjuvant therapy and selection criteria for different treatments. Survival will be influenced by both tumour biology and therapy. This important consideration must be remembered when analysing new markers, particularly in small studies.

Computerized local dental anesthetic systems: patient and dentist satisfaction.

A computer controlled dental anesthetic delivery system was studied with the OBJECTIVE of evaluating and comparing the unit to the traditional method of anesthetic delivery. The research design and METHOD of study involved the use of trained dentists who used both types of delivery systems on patients seen during their routine practice of dentistry. After the dental appointment was finished each dentist completed a survey concerning the injection. Patients completed a survey before the injection concerning their previous anesthetic experiences and completed another survey at the end of the dental appointment concerning the injection they had just received. Statistical analyses yielded RESULTS showing the two methods were rated very similarly by both patients and dentists. CONCLUSIONS resulting from the study are that computer controlled dental anesthetic injections and traditional anesthetic injections were accepted equally well by both dentists and patients.

Apoptosis, ageing and cancer susceptibility.

We have previously shown that peripheral blood lymphocytes (PBL) from individuals carrying a germline TP53 mutation show a dramatically reduced apoptotic response to radiation. As part of a study of this phenomenon, we also investigated apoptotic response in a series of breast cancer patients lacking TP53 mutations and in a control group of individuals without cancer. There was a significant reduction in mean apoptotic response with increasing age in all groups. These findings are consistent with a number of studies in rodents, which have demonstrated a reduction in DNA damage-induced apoptosis with increasing age. In addition, after adjusting for age, breast cancer patients showed significantly reduced apoptotic responses compared with normal controls (P=0.002). The odds ratio for breast cancer in women with an apoptotic response of <35%, compared with women with a response of >49%, was 6.42 (95% CI 1.68-24.6). The data further support the hypothesis that a reduction in apoptotic response to DNA damage with increasing age may play a significant role in the age-related increase in cancer.

Lack of mutations within ST7 gene in tumour-derived cell lines and primary epithelial tumours.

ST7 is a candidate tumour suppressor gene at human chromosome locus 7q31.1. We have performed mutational analysis of ST7 in a wide-range of cell lines and primary epithelial cancers and detected only one missense change in a breast cancer cell line. Other mutations previously found in cell lines and primary tumours were not evident in our analysis. These results imply that another tumour suppressor gene at this locus may be more important than ST7 in carcinogenesis.

BAG-i expression in human breast cancer: interrelationship between BAG-1 RNA, protein, HSC70 expression and clinico-pathological data.

BAG-1 (BCL-2 athanogene-1), a multifunctional protein which associates with steroid hormone receptors (including the oestrogen receptor) and the anti-apoptotic BCL-2 protein, regulates steroid hormone-dependent transcription and apoptosis. Direct interaction with 70 kD heat-shock proteins, HSC70 and HSP70, may mediate the diverse functions of BAG-1. Immunohistochemistry was used to examine the expression of BAG-1 and HSC70 in 160 cases of invasive breast cancer. BAG-1 was expressed in 92% of cases; most tumours exhibited cytoplasmic BAG-1, while a smaller proportion also had nuclear immunostaining. There was a significant inverse correlation between histological grade and nuclear BAG-1 expression, with higher-grade tumours tending to have reduced nuclear BAG-1 expression, but there was no association with cytoplasmic BAG-1. There was also no significant correlation between nuclear or cytoplasmic BAG-1 expression and oestrogen receptor positivity. Since BAG-1 may be influenced by hormonal background, the relationship between grade and oestrogen receptor was examined separately in pre-menopausal and post-menopausal women. The statistically significant correlation between nuclear BAG-1 expression and low tumour grade was strong in pre-menopausal, but not apparent in postmenopausal women. A statistically significant correlation was observed between cytoplasmic, but not nuclear, BAG-1 expression and oestrogen receptor status in pre-menopausal, but not postmenopausal, women. There was no correlation between BAG-1 protein expression and RNA, suggesting that important post-transcriptional mechanisms control BAG-1 expression in vivo. HSC70 was also detected in the majority (97%) of cases, although expression was not correlated with BAG-1 levels, oestrogen receptor status or tumour grade. Overall survival in cases with high levels of nuclear BAG-1 expression was improved, though not significantly. These results are consistent with the hypothesis that BAG-1 plays an important but variable role in breast cancers developing in pre-menopausal and post-menopausal women.

Investigations on a clinically and functionally unusual and novel germline p53 mutation.

This report describes an individual with a rare choroid plexus papilloma in adulthood (age 29) after earlier having an osteosarcoma (age 22). The results from this study, and others, suggest that it may be advisable to consider the possibility of a germline p53 mutation in adults presenting with choroid plexus tumours. In the current study automated DNA sequencing of genomic DNA detected a novel germline 7 base pair insertion in exon 5 of the p53 gene in this patient. The alteration in frame would produce amino acid substitutions beginning with alanine to glycine at position 161 and a stop codon at position 182 in the mutated protein. Surprisingly two assays of p53 function gave apparently wild-type results on peripheral blood lymphocytes from this individual. These results led us to carry out more detailed functional tests on the mutant protein. The mutant allele was expressed either at very low levels or not at all in phytohaemagglutinin stimulated lymphocytes. Further, the mutant protein was completely non-functional in terms of its ability to transactivate a series of p53-responsive genes (p21(WAF1), bax, PIG3), to transrepress a target gene and to inhibit colony growth in transfected Saos-2 cells. However, surprisingly, data from irradiated peripheral blood lymphocytes and transfected Saos-2 cells, suggested that this truncated, mutant protein retains significant ability to induce apoptosis.

Protein metabolism during an acute phase response in chickens.

Fractional rates of liver, muscle, plasma and acute phase portein synthesis were measured in chickens injected with saline or E. coli lipopolysaccharide (LPS). Male Single Comb White Leghorns were infused with a primed constant infusion of 15N-L-methionine and 2H5-L-phenylalanine into the portal vein for 2 h. Changes in plasma amino acid enrichment were similar for both amino acids reaching an apparent plateau by the 30 min sampling time. The enrichment of plasma protein-bound amino acid was measurable after 1 h of isotope infusion and increased linearly over 2h. LPS injection decreased free phenylalanine enrichment in the carotid artery (50%), and reduced tissue free methionine enrichment in the liver, pectoralis, and gastrocnemius by 16, 41, and 31% respectively. Isotopic enrichment of phenylalanine in liver protein, plasma protein and hemopexin increased in LPS injected birds relative to control birds. Fractional rates of muscle protein synthesis were not affected by LPS injection, however, liver protein, plasma protein, and hemopexin fractional synthesis rates increased 141, 161 and 266% respectively compared with untreated animals.

Mitotic counts provide additional prognostic information in grade II mammary carcinoma.

The ability to predict how long a patient diagnosed with breast cancer is likely to survive is still imprecise, despite numerous studies which have identified potential prognostic markers. The "established" markers such as nodal status, tumour size, and histological grade have been used for many years and certainly provide some degree of accuracy upon which treatment can be based. However, women with similar prognostic features can vary significantly in their outcome and very few of the newly identified markers provide information that is sufficiently useful to warrant the time and expense spent on their evaluation. In a cohort of 145 women, an assessment has been made of whether knowledge of the proliferative activity of grade II infiltrating ductal breast carcinomas can improve the accuracy of predicting clinical outcome for individual patients. Use of the mitotic count (MC), which was assessed as part of the grading system, enabled patients to be stratified into "good" and "bad" prognostic groups. The measurement of S-phase fraction using flow cytometry gave a similar result, but has the disadvantage that the technique requires specialized equipment. The evaluation of Ki-67 expression using immunohistochemistry was of no additional prognostic value in this defined group. It is proposed that MC, used once to establish grade, could be used again amongst the grade II tumours to improve the accuracy of prognosis and thus influence treatment strategies with minimal additional effort or expense.

Expression of P-glycoprotein in the chicken.

The multidrug resistance gene product, P-glycoprotein, may act as a defense mechanism against natural and man-made environmental toxins. Like mammals, chickens show high levels of P-glycoprotein expression in the liver, small intestine, and kidney. Expression of P-glycoprotein rapidly increased with age in the liver and kidney reaching a plateau by 2 and 4 days of age, respectively; however, expression of P-glycoprotein in the duodenum did not significantly change with age. Addition of dietary antibiotics (monensin, bacitracin), as models for dietary toxins, altered P-glycoprotein expression. Monensin increased P-glycoprotein expression in the liver and duodenum. Bacitracin reduced P-glycoprotein expression by 45% in the liver, but did not alter expression in the duodenum. Intraperitoneal injection of E. coli lipopolysaccharide, a model for acute inflammation, rapidly increased expression of Pgp protein in the liver ( approximately 2-fold). Expression then declines to pre-induction levels by 24 h. Similar responses were observed in the spleen and kidney but not the duodenum. These results confirm the presence of an avian P-glycoprotein homologue and suggest that dietary constituents regulate the expression of P-glycoprotein. Changes in P-glycoprotein expression may represent an important physiological response to foods containing toxins and an important component of the acute phase immune response.

Effects of biogenic amines on growth and the incidence of proventricular lesions in broiler chickens.

Biogenic amines have been implicated in a malabsorption syndrome characterized by decreases in feed efficiency and enlargement of the proventriculus. Two studies were conducted to determine the effects of two common biogenic amines, histamine (HIS) and cadaverine (CAD), on broiler growth and the incidence of pathologies associated with proventriculitis. In the first experiment, broiler chicks were fed diets containing 0, 0.01, 0.05, 0.1, and 0.2% HIS, and in the second experiment chicks were fed diets containing 0, 0.1, and 0.2% HIS, 0.1% CAD, or a combination of 0.1% HIS and 0.1% CAD. Histamine at 0.1 and 0.2% or the combination of HIS and CAD (0.1% each) reduced body weight and feed conversion at 21 d of age. Histamine (0.2%) or the combination of 0.1% HIS and 0.1% CAD increased the circumference of the gastric isthmus 14 and 16%, respectively, and the relative weight of the proventriculus by 21 and 36%, respectively. Histamine and CAD increased the total number, incidence, and severity of gizzard erosion and proventricular ulcers (plaques), and decreased the prominence of gastric papillae by 9 to 108%, depending on the lesion and level of biogenic amine. Dietary HIS (0.2%) increased putrescine by 91% and spermidine by 41% in proventriculus, and dietary CAD increased tissue CAD to detectable levels. Analysis of 49 commercially available, animal by-product feedstuffs suggests that if biogenic amines were the singular cause of proventriculitis, the current industry levels of dietary animal protein (5 to 10%) would not compromise growth performance.

Retention of the expression of E-cadherin and catenins is associated with shorter survival in grade III ductal carcinoma of the breast.

Many studies have investigated the relationship between the E-cadherin/catenin axis and breast cancer biology and yet, unlike the studies in other tumour systems, which have shown a relationship between down-regulation and poor survival, no clear association has emerged in breast. Since accumulating evidence suggests that ductal carcinoma of no special type (NST) represents a diverse group of biologies, this study has focused on grade III ductal carcinoma, in order to reduce the heterogeneity of the study population. A total of 470 breast tumours were studied. Consecutive sections were labelled with antibodies which recognize E-cadherin and the arm proteins with which it interacts: alpha-, beta-, and gamma-catenin. Membrane-bound and cytoplasmic E-cadherin and membrane-bound alpha-catenin expression were associated with a positive oestrogen receptor (ER) status, gamma-catenin with a negative ER status, and, surprisingly, all three with poor survival. Taken together, these findings suggest that a conserved E-cadherin/catenin axis may play a part in determining adverse outcome in grade III breast carcinoma.

Study of interlaboratory reliability and reproducibility of estrogen and progesterone receptor assays in Europe. Documentation of poor reliability and identification of insufficient microwave antigen retrieval time as a major contributory element of unreliable assays.

Immunohistochemical assays for estrogen receptors (ERs) and progesterone receptors (PRs) have not been surveyed for technical validity. In the present study, the reliability of the immunohistochemical assay for ER and PR was evaluated using data from 105 laboratories participating in external quality assessment (EQA) during a 2-year period. Technical variables associated with reliable immunostaining were analyzed. The efficiency of the antigen retrieval step was identified as the single most important contributory factor influencing the overall reproducibility of the assays. Reliable assays were found in 24 (36%) of 66 laboratories participating in continual EQA, including the majority of centers known to have clinically validated results. Inadequate assay sensitivity, with subsequent weak staining, was the main cause of poor and variable results by laboratories using microwave antigen retrieval; too short a heating time was identified as the principal contributory factor. Extension of the heating time resulted in significant improvement regardless of all other variables in the immunohistochemical protocol. Continual participation in EQA is an effective means for identifying and ameliorating variables that influence the reliability of immunohistochemical assays for predictive markers, thereby assisting in technical validation and standardization.