NON-SPECIFIC INHIBITORS OF NITRIC OXIDE SYNTHASE CAUSE MYOCARDIAL NECROSIS IN THE RAT

1. To study the effect of acute nitric oxide (NO) inhibition on the rat heart both in vitro and in vivo, male Wistar rats received a single bolus injection of saline, N^ω-nitro-L-arginine methyl ester (L-NAME; 0.5,1.5,5.0,15.0 and 45.0 mg/kg) and D-NAME (45.0mg/kg). 2. Animals were killed 72 h after the bolus injection of L-NAME and the hearts were removed and studied under light microscopy. In other groups of animals, saline, L-NAME and D-NAME were administered as above and the mean arterial blood pressure (MABP/carotid) was recorded. Furthermore, L-NAME was also administered in the drinking water (20 mg/kg per day) for 72 h and animals were then killed and their hearts evaluated as described above. Hearts of control animals were perfused in vitro and coronary flow was measured following saline, L-NAME (45 μg/heart) and D-NAME (45 μ/heart). 3. Areas of necrosis were observed in the left ventricle of animals that had received L-NAME at 5.0, 15.0 and 45.0 mg/kg. Also, only doses higher than 1.5 mg/kg caused an important increase in MABP. The frequency and extent of the lesions paralleled the dose of L-NAME administered and no lesions were observed in D-NAME- and saline-treated animals. 4. The oral administration of L-NAME also caused myocardial lesions similar to those described above, but the frequency and extent of these lesions were more discrete compared with those observed following 5.0 mg/kg, i.v., L-NAME. 5. Bolus injection of L-NAME into control rat hearts in vitro resulted in a small and transient fall in coronary flow (17.2 ± 1.4 and 12.2 ± 1.2 mL/min before and after L-NAME administration, respectively) within 30 s and this was followed 4.5 min later by a further (11.5 ± 1.6 mL/min) decrease. The administration of D-NAME to control hearts caused no change in coronary flow. 6. In conclusion, the acute inhibition of NO biosynthesis by L-NAME causes myocardial necrosis. Both high levels of MABP and a small but significant reduction in coronary flow (associated or not) can be responsible for the lesions we found.     

Susceptibility of 129/SvEv mice in two-stage carcinogenesis protocols to 12-O-tetradecanoylphorbol-13-acetate promotion

Embryonic stem cells derived from various derivatives of the murine 129/J strain are commonly used in the generation of knockout mice. Topical twice-weekly treatment of the 129/SvEv subline with either 2 or 5 microg of 12-O-tetradecanoylphorbol-13-acetate (TPA) for 4 weeks resulted in a sustained inflammation and hyperplasia. Identically treated C57BL/6 mice developed weaker inflammatory and hyperplastic responses over the same treatment course, and did not exhibit a sustained hyperplasia. SSIN mice treated with either 0.5 or 2 microg of TPA developed a sustained hyperplasia comparable to that seen in 129/SvEv mice, but a weak inflammatory response. Myeloperoxidase (MPO) measurements indicated dramatic infiltrations of the skins of all three murine strains by neutrophils within 48 h of a single TPA application. MPO activities remained significantly elevated in the skins of 129/SvEv mice and C57BL/6 mice following eight TPA treatments. In contrast, MPO activities in 8 X treated SSIN skins were comparable to those measured in solvent controls. 129/SvEv mice readily developed papillomas in two- stage skin carcinogenesis protocols employing DMBA as the initiator and TPA as the promoter. Papilloma incidences and multiplicities were dose- responsive with respect to promoter (using twice weekly applications of 1, 2 or 5 microg of TPA). With a promoting dose of 5 microg of TPA > or = 90% of the mice developed papillomas within 13 weeks, and maximum tumor multiplicities were reached within 18 weeks. These latter results, when compared to the published responses of other murine stocks and strains, demonstrate that 129/SvEv mice are very sensitive to TPA promotion in two-stage skin carcinogenesis protocols.      

Alterations of neonatal thyroid function

Grüters A, Krude H, Biebermann H, Liesenkötter KP, Schöneberg T, Gudermann T. Alterations of neonatal thyroid function. Acta Pædiatr 1999; Suppl 428: 17–22. Stockholm. ISSN 0803–5326
Recent progress has been made in understanding the pathogenesis of neonatal thyroid disorders. Autosomal recessive inheritance of mutations of the thyroid peroxidase and thyroglobulin genes has been described in some patients with congenital hypothyroidism (CH) and a family history of CH. Autosomal recessive inheritance of mutations of the thyrotrophin (TSH) receptor gene has also been reported in patients with CH and thyroid hypoplasia, and autosomal dominant mutations of the PAX8 gene have been described in patients with different forms of thyroid dysgenesis. These discoveries are important for patients with CH diagnosed by neonatal screening, as these patients will have normal fertility. The molecular genetic analysis of mutations of the TSH gene in patients with familial and sporadic cases of isolated central CH, who are missed by TSH screening programmes, now enables rapid diagnosis and appropriate therapy in the neonate. In newborn infants with severe non-autoimmune hyperthyroidism, autosomal dominant gain-of-function mutations in the TSH receptor gene have been demonstrated. In these patients, molecular genetic studies are extremely helpful in therapeutic decision making, as early thyroid ablation is the only effective treatment that avoids the sequelae of long-term hyperthyroidism. Molecular genetic studies are therefore useful in the diagnostic work-up of neonatal thyroid alterations. □ Congenital hypothyroidism, molecular pathogenesis, neonatal hyperthyroidism     

Repeated dose inhaled budesonide versus placebo in the treatment of croup

OBJECTIVE: To investigate the efficacy and tolerance of 12-hourly dosing with 2 mg 4 mL-1 of inhaled budesonide versus placebo in patients admitted to hospital with moderate/severe croup. METHOD: Eighty-two children hospitalised with croup received either 2 mg 4 mL-1 of budesonide or placebo 12 hourly (maximum four doses) via Ventstream nebuliser in a randomised, double-blind manner. Croup scores were performed at 0, 2, 6, 12, 24, 36 and 48 h from initial nebulisation whilst the patient remained hospitalised. Follow-up assessments were made 1 and 3 days after discharge. RESULTS: Improvement was observed in the budesonide group over the 12-h dosing interval when compared to placebo (P = 0.04). Time to attain a significant clinical improvement was superior in the budesonide group (P = 0.01). Three days after discharge seven of 32 placebo-treated patients and one of 34 budesonide-treated patients had sought further medical follow-up (P = 0.02). CONCLUSION: Twelve-hourly dosing with inhaled budesonide significantly improved symptoms of croup as well as decreased relapse rates when compared with placebo.     

Muir–Torre syndrome-associated pleomorphic liposarcoma arising in a previous radiation field

Muir–Torre syndrome is a variant of Lynch syndrome, characterised by sebaceous neoplasia and/or keratoacanthomas associated with visceral malignancies. Muir–Torre syndrome is caused by germline mutations of one of the mismatch repair genes, frequently MSH2 and less frequently MLH1 and MSH6. Visceral malignancies associated with Muir–Torre syndrome and Lynch syndrome include colorectal, endometrial and other gastrointestinal, urological and gynaecological malignancies. Small numbers of Lynch syndrome-associated soft tissue sarcomas have been reported, but there are no reported cases of soft tissue sarcomas in Muir–Torre syndrome. In this study, we report a 74-year-old man with known Muir–Torre syndrome with confirmed MSH2 germline mutation, diagnosed with pleomorphic liposarcoma of the right buttock in a previous radiation field. The tumour showed loss of expression of MSH2 and MSH6 on immunohistochemistry. Immunohistochemistry on another pleomorphic liposarcoma in a different patient with no previous history of Muir–Torre syndrome or Lynch syndrome showed no loss of expression of mismatch repair proteins. This is the first report of Muir–Torre syndrome-associated sarcoma and the first case of post-radiation sarcoma in Lynch syndrome.     

The C5a anaphylatoxin receptor CD88 is expressed in presynaptic terminals of hippocampal mossy fibres

Background  

In the periphery, C5a acts through the G-protein coupled receptor CD88 to enhance/maintain inflammatory responses. In the brain, CD88 can be expressed on astrocytes, microglia and neurons. Previous studies have shown that the hippocampal CA3 region displays CD88-immunolabelling, and CD88 mRNA is present within dentate gyrus granule cells. As granule cells send dense axonal projections (mossy fibres) to CA3 pyramidal neurons, CD88 expression could be expressed on mossy fibres. However, the cellular location of CD88 within the hippocampal CA3 region is unknown.