The effect of prophylactic tranexamic acid on the incidence of postoperative hemorrhage in greyhounds.

To investigate whether the incidence of postoperative hemorrhage in greyhounds was reduced when a standardized protocol for prophylactic tranexamic acid (TXA) administration to greyhounds undergoing surgery was followed, a retrospective clinical study at a private referral and first opinion hospital group was performed. Patient records of client-owned greyhounds undergoing elective surgery or dental procedures involving extractions were examined retrospectively, and 58 incidents of surgery considered eligible were documented, along with any subsequent reports of hemorrhage and whether the TXA protocol was followed. The use of TXA was not associated with a reduction in the incidence of postoperative hemorrhage in this population of greyhounds. In the group that did not receive TXA, post-operative hemorrhage was reported in 7/37 (18.9 %) cases and in the prophylactic TXA group, post-operative hemorrhage was reported in 11/21 (52.4 %) cases, a significantly higher number than in the group that did not receive TXA. Interestingly, in our population, prophylactic administration of TXA was not associated with a reduction in post-operative hemorrhage, but with a higher incidence of hemorrhage. We belief that descrepencies in our dataset may explain these findings, and a prospective randomized-controlled trial should be performed to further investigate the efficacy of TXA as an antifibrinolytic agent in greyhounds.

First report of suspected glycogen storage disease type 1a occurring in an adult dog.

A 4-year-old female border collie was presented with haemoabdomen following the rupture of a hepatocellular carcinoma. After referral for ongoing elevation of alanine aminotransferase and alkaline phosphatase, the dog was found to have marked vacuolar hepatopathy due to glycogen accumulation within the liver, fasting hypoglycaemia and hyperlactataemia, and a negative response to glucagon stimulation testing. These changes were strongly suggestive of glycogen storage disease type 1a. Based on our literature search, this report documents the first adult canine to be diagnosed with suspected glycogen storage disease type 1a.

Third-degree atrioventricular block with narrow QRS complexes in a case of hypoadrenocorticism in a dog.

A 4-year-old dog presented with lethargy and bradycardia (heart rate 40 bpm). Electrocardiogram diagnosed third-degree atrioventricular block with narrow QRS complexes. An atropine response test did not result in a change of the heart rate. Venous blood gas documented moderate hyperkalaemia and an adrenocorticotrophic hormone stimulation test was consistent with hypoadrenocorticism. The patient repeatedly converted to sinus rhythm with normalisation of serum potassium levels following medical treatment. This is the first report of third-degree atrioventricular block in a patient with hypoadrenocorticism that was not vagally mediated and did not require pacemaker implantation, with conversion to sinus rhythm following treatment of the hyperkalaemia.

Ehrlichia canis infection in a dog with no history of travel outside the United Kingdom.

A two-year-old female neutered Tibetan terrier was referred following a one-month history of lethargy, inappetence and pancytopenia, which had been poorly responsive to immunosuppressive and fluoroquinolone treatment. The dog was diagnosed with pure red cell aplasia and was found to be positive for Ehrlichia canis by both antibody titre measurement and polymerase chain reaction. The dog lived in London and had not travelled outside the UK. The dog was treated with doxycycline, prednisolone and ciclosporin, but died as a result of gastrointestinal tract haemorrhage. To the authors' knowledge, this represents the first reported case of Ehrlichia canis in a dog in the UK with no previous travel history.

Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study).

BACKGROUND: Multiple questionnaires to screen for psoriatic arthritis (PsA) have been developed but the optimal screening questionnaire is unknown. OBJECTIVES: To compare three PsA screening questionnaires in a head-to-head study using CASPAR (the Classification Criteria for Psoriatic Arthritis) as the gold standard. METHODS: This study recruited from 10 U.K. secondary care dermatology clinics. Patients with a diagnosis of psoriasis, not previously diagnosed with PsA, were given all three questionnaires. All patients who were positive on any questionnaire were invited for a rheumatological assessment. Receiver operating characteristic (ROC) curves were used to compare the sensitivity, specificity and area under the curve of the three questionnaires according to CASPAR criteria. RESULTS: In total, 938 patients with psoriasis were invited to participate and 657 (70%) patients returned the questionnaires. One or more questionnaires were positive in 314 patients (48%) and 195 (62%) of these patients attended for assessment. Of these, 47 patients (24%) were diagnosed with PsA according to the CASPAR criteria. The proportion of patients with PsA increased with the number of positive questionnaires (one questionnaire, 19·1%; two, 34·0%; three, 46·8%). Sensitivities and specificities for the three questionnaires, and areas under the ROC curve were, respectively: Psoriatic Arthritis Screening Evaluation (PASE), 74·5%, 38·5%, 0·594; Psoriasis Epidemiology Screening Tool (PEST), 76·6%, 37·2%, 0·610; Toronto Psoriatic Arthritis Screen (ToPAS), 76·6%, 29·7%, 0·554. The majority of patients with a false positive response had degenerative or osteoarthritis. CONCLUSION: Although the PEST and ToPAS questionnaires performed slightly better than the PASE questionnaire at identifying PsA, there is little difference between these instruments. These screening tools identify many cases of musculoskeletal disease other than PsA.

Multi-technique comparison of source and primary transfer soil samples: an experimental investigation by D Croft and K Pye. A comment.

The Croft and Pye paper has a story to tell about the differentiation capabilities of four analytical techniques. It is not however, the whole story. This may be due in part to the lack of reproducibility in the generation of results, and also in the effort to match soil samples and thus infer that the results provide stronger conclusions than is possible to make with this sort of analysis. More research must be done to establish in what instances these techniques and others provide reliable, reproducible, representative and accurate results, and in what capacity such results can be presented. As they stand, the results from this paper should be treated with great caution and not extrapolated to any other forensic case work until greater reliability of these and other techniques has been established.

When typical is atypical: mycobacterial infection mimicking cutaneous vasculitis.

Patients with systemic lupus erythematosus (SLE) who present with skin disease pose the clinician with diagnostic challenges. The skin disease can reflect an increase in systemic disease activity suggested by other features of active lupus and, as such, usually responds well to more aggressive immunosuppressive therapy. Other possibilities of skin disease include drug eruptions, skin disease unrelated to SLE and, more rarely, opportunistic skin infection. In patients who show a poor response to more aggressive immunosuppressive therapy, consideration must be given to the possibility of opportunistic infection. A high index of suspicion will allow prompt treatment. We describe two patients with SLE who developed cutaneous atypical mycobacterial infection during immunosuppressive therapy. The diagnosis of cutaneous vasculitis was considered in both cases, but subsequent skin biopsy revealed the correct diagnosis. This report illustrates the importance of skin biopsy in patients with suspected cutaneous lupus who are not responding to immunosuppressive therapy.

Monoclonal antibodies to the carboxy-terminal Ea sequence of pro-insulin-like growth factor-IA (proIGF-IA) recognize proIGF-IA secreted by IM9 B-lymphocytes.

Insulin-like growth factor-I (IGF-I) circulates in human serum as a 7 kDa peptide but analysis of IGF-I cDNAs predicts two pro-hormone precursors (proIGF-IA and proIGF-IB) with distinct C-terminal E domains. The function of these precursors, and the E peptides generated on cleavage to mature IGF-I, is unknown, largely because of a lack of tools for distinguishing precursors from constituent peptides. We used a synthetic Ea peptide to develop monoclonal antibodies (MAbs) which can recognize the carboxy-terminal sequence of proIGF-IA. These were characterized using proIGF-IA generated by transfected HEK293 cells. The anti-proIGF-IA MAbs immunoprecipitated two peptides (19--21 and 14 kDa) which were also recognized by MAbs to mature IGF-I. The proIGF-IA MAbs could also detect peptides of 9 and 4 kDa predicted to be Ea peptides. Treatment with N -glycosidase proved the 19--21 kDa and 9 kDa bands to be glycosylated proIGF-IA and Ea peptide respectively. Using these antibodies, we have identified proIGF-IA secreted from the IM9 B-lymphocyte cell line. This work paves the way for studies on proIGF-IA and Ea peptide regulation and function.

Prohormones: their clinical relevance.

The majority of peptide hormones and neuropeptides are synthesized as precursors, which are cleaved in a sequence-specific and tissue-specific manner to yield the biologically active peptides. There has been considerable progress in the past ten years in understanding the nature and mechanism of action of the prohormone convertases that cleave these prohormones. Evidence from knockout technology and clinical examples of gene mutations has provided functional information on disruption of prohormone cleavage and the bioactivity of prohormones. There are specific examples of the clinical relevance of circulating prohormones, such as adrenocorticotrophin (ACTH) precursors and proinsulin. The central issues that still remain are: (1) What is the relative importance of each of the different processing pathways and processing enzymes in regulating hormone action? (2) How do the serum concentrations of prohormones compare with the mature hormone levels? (3) What are the biological consequences of prohormones in the circulation?

Structural variation of the pseudoautosomal region between and within inbred mouse strains.

The pseudoautosomal region (PAR) is a segment of shared homology between the sex chromosomes. Here we report additional probes for this region of the mouse genome. Genetic and fluorescence in situ hybridization analyses indicate that one probe, PAR-4, hybridizes to the pseudoautosomal telomere and a minor locus at the telomere of chromosome 9 and that a PCR assay based on the PAR-4 sequence amplifies only the pseudoautosomal locus (DXYHgu1). The region detected by PAR-4 is structurally unstable; it shows polymorphism both between mouse strains and between animals of the same inbred strain, which implies an unusually high mutation rate. Variation occurs in the region adjacent to a (TTAGGG)n array. Two pseudoautosomal probes can also hybridize to the distal telomeres of chromosomes 9 and 13, and all three telomeres contain DXYMov15. The similarity between these telomeres may reflect ancestral telomere-telomere exchange.

CENP-B binds a novel centromeric sequence in the Asian mouse Mus caroli.

Minor satellite DNA, found at Mus musculus centromeres, is not present in the genome of the Asian mouse Mus caroli. This repetitive sequence family is speculated to have a role in centromere function by providing an array of binding sites for the centromere-associated protein CENP-B. The apparent absence of CENP-B binding sites in the M. caroli genome poses a major challenge to this hypothesis. Here we describe two abundant satellite DNA sequences present at M. caroli centromeres. These satellites are organized as tandem repeat arrays, over 1 Mb in size, of either 60- or 79-bp monomers. All autosomes carry both satellites and small amounts of a sequence related to the M. musculus major satellite. The Y chromosome contains small amounts of both major satellite and the 60-bp satellite, whereas the X chromosome carries only major satellite sequences. M. caroli chromosomes segregate in M. caroli x M. musculus interspecific hybrid cell lines, indicating that the two sets of chromosomes can interact with the same mitotic spindle. Using a polyclonal CENP-B antiserum, we demonstrate that M. caroli centromeres can bind murine CENP-B in such an interspecific cell line, despite the absence of canonical 17-bp CENP-B binding sites in the M. caroli genome. Sequence analysis of the 79-bp M. caroli satellite reveals a 17-bp motif that contains all nine bases previously shown to be necessary for in vitro binding of CENP-B. This M. caroli motif binds CENP-B from HeLa cell nuclear extract in vitro, as indicated by gel mobility shift analysis. We therefore suggest that this motif also causes CENP-B to associate with M. caroli centromeres in vivo. Despite the sequence differences, M. caroli presents a third, novel mammalian centromeric sequence producing an array of binding sites for CENP-B.

YAC cloning Mus musculus telomeric DNA: physical, genetic, in situ and STS markers for the distal telomere of chromosome 10.

Three Mus musculus DBA/2 YAC libraries were constructed using a half-YAC telomere cloning vector. This functional complementation approach yields libraries which include terminal restriction fragments of the mouse genome. Screening all three libraries led to the isolation of 32 independent clones which carry linear YACs containing the mouse terminal repeat sequence, (TTAGGG)n. These YACs provide a resource to isolate regions of the mouse genome close to chromosome termini and excluded from existing conventional YAC libraries. To demonstrate their utility, a hybridization probe was isolated from Mtel-1, the first (TTAGGG)n-containing YAC isolated. This probe detects a approximately 70 kb Kpnl fragment in the mouse genome which is sensitive to pretreatment with BAL31 exonuclease. A PCR-based genetic marker generated from the sequence of this probe maps 4.4 cM from the most distal anchor locus on chromosome 10 in the EUCIB interspecific backcross. STS primers for this locus, D10Hgu1, were used to isolate YAC 110F4 from a commercially available mouse YAC library. Fluorescence in situ hybridization demonstrates that YAC 110F4 hybridizes to the distal telomere of chromosome 10. Clones in this collection of telomere YACs therefore partially overlap clones in conventional YAC libraries, and thus the previously unavailable terminal regions of the mouse genome can now be linked with the developing mouse STS YAC contig. Genetic markers such as D10Hgu1 allow the ends of the mouse genetic map to be defined, thus closing the map.

Mouse centromere mapping using oligonucleotide probes that detect variants of the minor satellite.

Cytologically, the centromere is found at the very end of most Mus musculus chromosomes, co-localizing with an array of minor satellite sequences. It is separated from the euchromatin of the long arm by a large domain of heterochromatin, composed in part of arrays of major satellite sequences. We used oligonucleotide probes that specifically detect regions of sequence variation found in certain cloned minor satellite sequences. They detect a limited subset of the minor satellite arrays in the mouse genome, based on both pulsed-field gel electrophoresis and in situ hybridization data, and provide direct molecular genetic markers for individual centromeres in some inbred mouse strains. Array size polymorphisms detected by these probes map to positions consistent with the centromeres of chromosomes 1 and 14 in the BXD recombinant inbred (RI) strains. The genetic distances between these minor satellite arrays and loci on the long arms of chromosomes 1 and 14 are consistent with repression of meiotic recombination in the heterochromatic domains separating them. The existence of chromosome-specific minor satellite sequences implies that the rate of sequence exchange between non-homologous chromosomes relative to the rate between homologous chromosomes is much lower than has previously been postulated. We suggest that the high degree of sequence homogeneity of mouse satellite sequences may instead reflect recent common ancestry.

Outcome of prophylactic and therapeutic cranial irradiation in disseminated small cell lung carcinoma: a Southwest Oncology Group Study.

The issue whether cranial radiotherapy (RT) should be used prophylactically (PCI) or therapeutically (TCI) in small cell lung carcinoma (SCLC) is considered controversial by some oncologists. Trying to clarify this issue we have performed a retrospective analysis of a Southwest Oncology Group (SWOG) protocol for disseminated SCLC. Three Hundred and seventy-seven cases had no evidence of metastases to the brain (MB). One hundred and forty four of those had PCI. Seventy one cases were diagnosed of MB, and 64 received TCI. We confirmed previous reports showing a low percentage of brain relapse with PCI (around 5%), with minimal immediate morbidity. We also confirmed a high percentage of objective response (90%) with TCI, (although we had no response information in 40% of them) with long duration of response of 33 weeks. Brain relapse after TCI was only 18%. Only long-term survivors had brain relapse as survival of relapsing patients was longer than those without brain relapse (45 weeks versus 33 weeks, p = 0.06). However, 20 (31%) of the 65 with initial MB died within 6 weeks of registration, some without completing RT to brain. In the majority, cause of death was considered related directly to brain damage, or indirectly as sepsis developed in patients whose poor performance status was considered to be caused by their brain symptoms. When comparing patients with and without MB, the former had (a) worse survival (24 versus 32 weeks, p = 0.02) and (b) higher proportion of patients with poor initial performance status (50% versus 34%, p = 0.04). Although the possibility of long-term morbidity with PCI is deterring some oncologists from recommending it, our data show that MB creates a real chance for immediate morbidity and this should not be ignored. The pros and cons of both approaches and some new recommendations for PCI are discussed.

Eosinophilic alveolitis in acute respiratory failure. A clinical marker for a non-infectious etiology.

Two patients with acute respiratory failure requiring mechanical ventilation were found to have eosinophilic alveolitis on bronchoalveolar lavage and lung biopsy studies. Neither patient had evidence of lung infection or parasitic disease and both rapidly improved following treatment with corticosteroids. Lung eosinophilia in this setting is unusual, since the stress reaction that accompanies severe illness usually causes a rapid drop in circulating eosinophil levels. Eosinophilic alveolitis in such patients may be a useful clinical marker for non-infectious acute lung injury that is responsive to corticosteroid therapy.

Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience.

To study the influence of chronologic age on treatment outcome in patients with advanced, diffuse large-cell (histiocytic) lymphoma (DHL), we reviewed the results of two recent Southwest Oncology Group (SWOG) clinical trials. From 1974 to 1982, members entered 307 eligible patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without bleomycin, and CHOP with or without immunotherapy using BCG, levamisole, or both. Complete response (CR) rates declined progressively with advancing age: 65% in those under 40, 60% in the 40 to 54 age group, 55% in the 55 to 64 age group, and 37% in those 65 and older (P = .001). Likewise, survival decreased significantly in older patients: medians were 101 +, 52, 34, and 16 months, respectively (P less than .001). Treatment guidelines included an initial dose reduction of 50% for patients aged 65 or older and for younger patients with bone marrow compromise. Despite protocol specifications, 23 of 81 patients aged 65 or older received initial full-dose therapy. When these patients were compared with younger patients on whom full-dose chemotherapy was started, survival curves, but not CR rates, were still significantly different. There were no significant differences in duration of CR or frequency of treatment complications. These data suggest that older age is associated with a worse prognosis in advanced DHL. Moreover, the initial dose reduction for patients aged 65 or older may have contributed to their inferior outcomes.

Low-dose deoxycoformycin in lymphoid malignancy.

Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase (ADA), was explored for its antineoplastic potential in 28 patients with advanced lymphoid malignancy. Both normal and malignant B lymphocytes have low levels of ADA activity, and low doses of dCF profoundly inhibit this enzyme in the peripheral blood of patients with chronic lymphocytic leukemia (CLL). The low doses of dCF administered in this trial (4 mg/m2) were not associated with prohibitive toxicity. Five of 28 patients had an objective response. Four additional patients had clinical improvement. No significant difference in the pretreatment ADA activity existed between responding patients and treatment failures. The demonstration of responses to dCF following failure on standard alkylating agents suggests that dCF may not be cross-resistant with current agents used to treat CLL. Additional studies should be pursued using low-dose dCF in patients with advanced malignancy.