Ovine forestomach matrix biomaterial is a broad spectrum inhibitor of matrix metalloproteinases and neutrophil elastase

Proteases play a critical role in the ordered remodelling of extracellular matrix (ECM) components during wound healing and tissue regeneration. However, the usually ordered proteolysis is compromised in chronic wounds due to over‐expression and high concentrations of matrix metalloproteinase's (MMPs) and neutrophil elastase (NE). Ovine forestomach matrix (OFM) is a decellularised extracellular matrix‐based biomaterial developed for tissue regeneration applications, including the treatment of chronic wounds, and is a heterogeneous mixture of ECM proteins and proteoglycans that retains the native structural and functional characteristics of tissue ECM. Given the diverse molecular species present in OFM, we hypothesised that OFM may contain components or fragments that inhibit MMP and NE activity. An extract of OFM was shown to be a potent inhibitor of a range of tissue MMPs (IC₅₀s = 23 ± 5 to 115 ± 14 µg/ml) and NE (IC₅₀ = 157 ± 37 µg/ml), and was more potent than extracts prepared from a known protease modulating wound dressing. The broad spectrum activity of OFM against different classes of MMPs (i.e. collagenases, gelatinases and stromelysins) may provide a clinical advantage by more effectively addressing the protease imbalance seen in chronic wounds.     

Capillary transit time heterogeneity and flow-metabolism coupling after traumatic brain injury

Most patients who die after traumatic brain injury (TBI) show evidence of ischemic brain damage. Nevertheless, it has proven difficult to demonstrate cerebral ischemia in TBI patients. After TBI, both global and localized changes in cerebral blood flow (CBF) are observed, depending on the extent of diffuse brain swelling and the size and location of contusions and hematoma. These changes vary considerably over time, with most TBI patients showing reduced CBF during the first 12 hours after injury, then hyperperfusion, and in some patients vasospasms before CBF eventually normalizes. This apparent neurovascular uncoupling has been ascribed to mitochondrial dysfunction, hindered oxygen diffusion into tissue, or microthrombosis. Capillary compression by astrocytic endfeet swelling is observed in biopsies acquired from TBI patients. In animal models, elevated intracranial pressure compresses capillaries, causing redistribution of capillary flows into patterns argued to cause functional shunting of oxygenated blood through the capillary bed. We used a biophysical model of oxygen transport in tissue to examine how capillary flow disturbances may contribute to the profound changes in CBF after TBI. The analysis suggests that elevated capillary transit time heterogeneity can cause critical reductions in oxygen availability in the absence of ‘classic'' ischemia. We discuss diagnostic and therapeutic consequences of these predictions.     

PROGNOSTIC SIGNIFICANCE OF THE CO-EXPRESSION OF p53 AND c-erbB-2 PROTEINS IN BREAST CANCER

The immunohistochemical expression of p53 and c-erbB-2 gene proteins was examined in a series of 130 breast adenocarcinomas. This study intended to investigate whether the frequency of the altered expression of the tumour suppressor gene p53 and the overexpression of the oncogene c-erbB-2 in breast cancer tissue cells correlated with other variables known to affect the biological behaviour of these tumours and the overall survival of the patients (median follow-up time: 6 years). The expression of p53 protein and c-erbB-2 gene product was evaluated immunohistochemically. Expression of p53 protein was detected in 30 (23 per cent) of the neoplasms examined, while 26 (20 per cent) out of the 130 cases demonstrated positive c-erbB-2 immunoreactivity. There was a statistically significant association between p53 protein expression and primary tumour size, lymph node involvement, and oestrogen receptor positivity. The incidence of c-erbB-2 positivity was significantly correlated with high tumour grade, axillary node invasion, large tumour size, and the absence of steroid receptors. p53 immuno-expression was clearly associated with c-erbB-2 protein overexpression. Concomitant p53 and c-erbB-2 positive immunolabelling, which emerged in 14 out of the 130 cases (10·7 per cent), was clearly associated with high grade, large size, positive nodal status, ductal infiltrating (NOS) histological type, and low values of progesterone receptors. Overall survival of patients was not significantly related to the immunoreactivity of either p53 or c-erbB-2 considered separately, whereas there was a clearly significant trend to worse overall prognosis in cancers with double p53/c-erbB-2 positive phenotype. The simultaneous immunodetection of p53/c-erbB-2 appears to have greater negative prognostic relevance than their separate expression.     

Immunohistochemical characterization of the 'intimal proliferation' phenomenon in Sneddon's syndrome and essential thrombocythaemia

Cellular changes were immunocytochemically characterized in skin vessels of five patients with idiopathic generalized racemose livedo (Sneddon's syndrome), and one patient with localized racemose livedo associated with essential thrombocythaemia. Antibodies against α-smooth muscle-actin, tropomyosin, desmin, vimentin, factor VIII-related antigen, human endothelial cells (CD31), human macrophages (CD68), and HLA-DR positive cells (CR3/43) were used. Conventional light microscopy showed, in all cases, intimal thickening of ascending arteries and arterioles as a result of an accumulation of cells and extracellular hyalinized material. None of the specimens showed infiltration with polymorphonuclear leucocytes or macrophages. The cells in the region of the intimal hyperplasia showed intense positive immunostaining for α-smooth muscle actin and tropomyosin. Staining for the intermediate filament desmin was localized to the resident smooth muscle cells of the media, whereas staining for vimentin was found in all types of cells in both the intima and media. Positive immunostaining for factor VIII-related antigen and CD31 was strictly confined to the endothelial cells lining the narrowed lumina of the vessels. No positive staining with either antibody was observed in totally occluded vessels. Cells in the subintimal space did not show reactivity for CD68 in any of the specimens, but two cases showed solitary cells with positive staining for HLA-DR in this region. There were no differences in staining pattern between Sneddon's syndrome and essential thrombocythaemia with any of the antibodies. Our results support the assumption that the ‘intimal proliferation’ in both diseases is caused by colonization of the subendothelial space with contractile cells of possibel smooth muscle origin. The similarities in histopathology and immunocytochemistry might indicate that in both diseases platelet-derived factors play a causative role.     

Elephantiasis nostras verrucosa: beneficial effect of oral etretinate therapy

Elephantiasis nostras verrucosa is characterized by chronic secondary, non-filarial lymphoedema due to recurrent lymphangitis, dermal fibrosis, and epidermal changes consisting of hyperkeratotic, verrucous and papillomatous lesions. Histologically, there is pseudoepitheliomatous hyperplasia. Therapeutic efforts should aim to reduce lymph stasis, which will also lead to improvement of the cutaneous changes. In this study, rapid disappearance of the hyperkeratotic and verrucous lesions, remarkable flattening of the papillomatous nodules and improvement of lymphoedema occurred in three obese patients treated with etretinate in an initial dose of 0.6-0.75 mg/kg/day for 4-6 weeks. Monitoring of plasma concentrations of etretinate, acitretin and 13-cis-acitretin by HPLC revealed sufficient short-time absorption (4 h) and bioavailability of the drug (30 days; two out of three patients). Long-term maintenance therapy in one patient produced a remarkable improvement in the lymphoedema; another patient relapsed after discontinuation of the etretinate and responded again after this was reintroduced. In the third patient treatment was withdrawn because of an increase in triglycerides, but improvement persisted 6 months later. The clinical side-effects of oral retinoid therapy were moderate and well tolerated.     

Genetic analysis of viral variants selected in transmission of human immunodeficiency viruses to newborns

Our previous studies have indicated that HIV transmission from infected mothers to infants occurs with viruses showing rapid kinetics of replication, and either resistance to maternal neutralizing antibodies or sensitivity to enhancing antibodies. The genotypic patterns that result in these and other phenotypic viral characteristics may provide clues to the selection pressures exerted during this mode of transmission. For this reason, DNA sequences of the envelope gene (env) were determined for viral isolates obtained from seropositive women who were mothers of either infected or uninfected infants. Sequences of viruses isolated early in life from the infected newborns were also determined, such that diversity both within isolates and between maternal and infant isolates could be assessed. Among isolates obtained from mothers of uninfected infants, the V3 region of env demonstrated a higher degree of heterogeneity than those from mothers of infected infants. Similar to the viruses obtained from the mothers of infected infants, the infant-derived viral sequences were relatively homogeneous. Finally, the reactivity of maternal plasma with infant-derived HIV isolates, whether via neutralizing or enhancing antibodies, appeared to predict the distribution of viral sequences in the infant isolates. These data suggest that selective pressure on HIV-1 during transmission or growth in the infected infant may be mediated by biologic and/or immunologic processes.     

Incidence, clinical significance and prognosis of ventricular fibrillation in the early phase of myocardial infarction

Of 1265 patients admitted to the CCU with the diagnosis of acuteMI, 96 (7.6%) developed ventricular fibrillation within 72 hoursfollowing admission. Of these 96, 35 (36.5%) had secondary VFassociated with left ventricular failure; they had a high in-hospitalmortality of 57.1%. The remaining 61 (63.5%) had primary VF,i.e. VF occurring in the absence of significant LV failure.Fourteen of these (23%) died in hospital: 9 due to PVF (3 duringthe first episode, 6 during a recurrence). This mortality figurewas significantly higher (P<0.001) than the mortality of10% seen among patients who did not experience VF. Primary VFshowed a recurrence rate of 20%. Compared with the 1061 patientswho left the hospital without primary VF, the 61 subjects withthis rhythm disorder were older, had larger infarcts and morefrequent complications, such as pericarditis, conduction abnormalities,frequent ventricular premature contractions and signs of rightventricular failure. These findings, in contrast with a widelyheld view, suggest that primary VFmay carry a guarded prognosis.