Prognostic value of MMP-2, -9 and TIMP-1,-2 immunoreactive protein at the invasive front in advanced head and neck squamous cell carcinomas

In head and neck cancer as well as in other carcinomas, tumor expansion and spread to distant sites require the secretion of destructive enzymes that degrade the extracellular matrix. A variety of proteases contribute to matrix destruction. Characteristics of the invasive tumor front may reflect tumor prognosis better than do other parts of the tumor. Therefore, it was the aim of the present study to (i) compare central and peripheral tumor zones for differences in the expression of matrix-metalloproteinases (MMP) -2 and -9 and their naturally occurring inhibitors (tissue inhibitor of matrix-metalloproteinases (TIMP) -1 and -2), (ii) examine the morphological potential of malignancy, and (iii) correlate these findings with clinicopathological parameters. The study population consisted of 106 surgical specimens of advanced head and neck squamous cell carcinomas. The invasive front was graded for malignancy, and immunohistochemical staining with MMP-2, MMP-9, TIMP-1 and TIMP-2 antibodies was performed. Both MMP-2 and MMP-9 were found to be significantly overexpressed at the tumor front. The MMP-2-positive invasive front exhibited diminished overall survival times. In multivariate analysis, MMP-2 expression retained its correlation with overall survival in addition to nodal status and total malignancy score. Expression of TIMP-2 correlated with local tumor invasion. We conclude that the expression of MMP-2 at the invasive front is a marker of poor survival and appears to be associated with early recurrence in initially lymph node-negative patients.     

Patients affected with Fabry disease have an increased incidence of progressive hearing loss and sudden deafness: an investigation of twenty-two hemizygous male patients

Background  

Fabry disease (FD, OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of alpha-galactosidase A, a lysosomal enzyme. While the progressive systemic deposition of uncleaved glycosphingolipids throughout the body is known to have protean clinical manifestations, few data are available regarding the cochlear involvement.     

Monoclonal antibodies specific for the bundle-forming pilus of enteropathogenic Escherichia coli.

The bundle-forming pilus (BFP) produced by enteropathogenic Escherichia coli (EPEC) is associated with the presence of a large EPEC adherence factor plasmid and the formation of localized adherence clusters on tissue culture cells. Three mouse monoclonal antibodies (ICA2, ICA3, and ICA4) were produced against BFP purified from EPEC B171 (O111:NM). These monoclonal antibodies reacted in immunoblots with different epitopes of the 19.5-kDa bundlin subunit of BFP of heterologous EPEC. These reagents could serve as diagnostic tools for the identification of EPEC as well as for studying the role of BfpA in the interaction of EPEC with eukaryotic cells.     

Effect of treatment with octreotide on the morphology of growth hormone—secreting pituitary adenomas: Study of 24 cases

Twenty-four acromegalic patients were treated with octreotide subcutaneously for periods of 3 to 6 weeks (group I, 12 cases) or 6 months (group II, 12 cases) before transsphenoidal surgery. Radiological studies performed in 19 patients before and at the end of this treatment period revealed no changes in 8 cases. In 8 other cases, a slight reduction in tumorsize was observed, and in 3 cases an important shrinkage was documented. At surgery, the adenomatous tissue appeared softer than in nonpretreated patients, facilitating the operation. Pathological examination revealed widening of perivascular spaces with accumulation of fibrous tissue and more crinophagy than in nonpretreated patients but failed to reveal morphologically pronounced cell involution as observed in prolactin-producing adenomas treated with dopamine agonists. No significant difference in frequency or extent of cellular changes was noted between the two groups. These morphological findings seem to be more consistent with a functional inhibition of growth hormone release than with cellular alterations induced by octreotide.     

Osteopathien und Calcium-Phosphat-Stoffwechsel bei chronischer Hämodialyse

Zusammenfassung Unter chronischer Hämodialyse-Behandlung wurden 13 Fälle auf Knochenveränderungen unter Berücksichtigung des Calcium-Phosphat-Stoffwechsels untersucht. Die Knochenveränderungen wurden histomorphometrisch definiert. Bestimmt wurden die prozentualen Anteile der neutralen Oberflächen, des Osteoids, der aktivierten Osteoblasten, der Resorptionslacunen und der mehrkernigen Osteoclasten an den endostalen Oberflächen, sowie die mittlere Breite der Osteoidsäume. Außerdem wurden Formation und Resorption des Knochens mittels quantitativer Mikroradiographie sowie die volumetrische Dichte der Spongiosa gemessen.Beiallen Fällen konnten unterschiedlich schwere Knochenveränderungen nachgewiesen werden (60% schwere und 40% leichte), wobei die stets pathologisch erhöhte Knochenresorption als Ausdruck eines regulativen sekundären Hyperparathyreoidismus gewertet wurde. Eine direkte Beziehung zwischen Calciumspiegel und Schwere der renalen Osteopathie ließ sich nicht beweisen. Die Hyperphosphatämien, die bei allen Patienten unter der Hämodialyse-Behandlung unverändert blieben, ergaben mit den ansteigenden Serumcalciumwerten pathologische Calciumphosphatprodukte. Bei einem Teil der Patienten kam es zu extraossären Verkalkungen, die unter kontrollierter Behandlung mit Aluminiumhydroxyd und abfallendem Calciumphosphatprodukt eine erhebliche Rückbildungstendenz zeigten. Wegen der Gefahr derartiger Calcifizierungen verbot sich in unserem Krankengut eine Vitamin D-Behandlung. Die Indikation einer totalen oder subtotalen Parathyroidektomie wurde in Abhängigkeit vom Ausmaß der Osteopathie und einer möglichen Nierentransplantation erörtert.

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Bone Disease and Calcium-phosphate Metabolism in Chronic Hemodialysis

Summary 13 patients under chronic hemodialysis were studied for changes in the bone, whereby calcium and phosphorus metabolism were given special attention. The changes in the bone were defined histomorphometrically. The percentage of the neutral surfaces, the osteoid, the activated osteoblasts, the resorption lacunae and the polynuclear osteoclasts of the endosteal surfaces were determined as well as the medium width of the osteoid seams. Moreover, formation and resorption of the bone were assessed by quantitative microradiography and the volumetric density of the cancellous bone was measured. Inall cases, bone changes of various degree were observed (60% of serious and 40% of slight changes), whereby the constantly increased bone resorption was considered as expression of a regulative secondary hyperparathyroidism. A direct relationship between serum calcium levels and the degree of seriousness of renal osteopathy could not be established. Hyperphosphatemia remained unchanged and with increasing serum calcium levels, the calcium phosphorus product became abnormally high in all subjects under hemodialysis. Extraosseus calcifications developed in some cases and were reduced to a considerable degree by controlled treatment with aluminiumhydroxide in connection with a fall of the calcium phosphorus product. Because of the risk of such calcifications, vitamin D treatment were out of question. Total or subtotal parathyroidectomy was discussed in relation to the degree of osteopathy and the possibility of a kidney transplantation.

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Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.     

The effects of hip contact aberrations on stress patterns within the human femoral head

A two-dimensional finite element model incorporating cancellous bone inhomogeneity is used to study femoral head stress alterations caused by changes from the usual articular contact patterns. The contact stress distributions, calculated from an earlier mathematical analysis by Greenwald and O'Connor (16), are found to influence not only the adjacent subchondral bone, but relatively distant parts of the head as well. Both abnormally large joint incongruity and abnormally low cartilage compliance cause load to shift away from the superior “weight-bearing” area, out toward the periphery of the contact region. As a consequence, transverse compressive stresses, which are of appreciable magnitude but which do not contribute to weight bearing, are built up throughout much of the superior and central portions of the femoral head. Most small changes in the overall cartilage thickness or in its thickness distribution, when considered in isolation from hip compliance changes, have only minor effects on the internal stress distribution. An important exception is cartilage thinning at the superior margin, which can result in abrupt longitudinal compressive stress concentrations. It is suggested that such alterations of the normal patterns of stress transmission may contribute to sclerosis or to the formation of osteophytes or cysts in the osteoarthritic hip. This study was aided by grants from the Easter Seal Research Foundation (#N7739), the National Science Foundation (#ENG78-05451), the Barra Foundation, Inc., and the Western Pennsylvania Chapter of the Arthritis Foundation. The authors wish to acknowledge the excellent service provided by the University of Pittsburgh Computer Center. The assistance of Mr. Gary E. Graf and Mrs. Diana W. Montgomery are also appreciated.     

Chronic intracranial pressure monitoring by telemetry: Clinical experience

Intracranial pressure (ICP) monitoring is a critical measure for avoiding severe brain dysfunction or brain death by directing supportive therapy so as to prevent ICP increase severe enough to reduce cerebral blood perfusion. Such situations occur with brain swelling, increased cerebral vascular volume, and increase in cerebrospinal fluid (CSF) volume. Causes include ischemic stroke, subarachnoid bleeding, brain contusion, encephalitis (as in Reye's syndrome), and hydrocephalus from meningitis or neoplasm. When several days of ICP monitoring can direct resolution of the pressure crisis, the invasive direct connection of an intracranial sensor with external recording device carries only minimal infection risk. Prolonged ICP monitoring for weeks or months demands telemetry and becomes desirable in a number of chronic disease problems including both congenital and acquired hydrocephalus where enlarged and pressurized cerebral ventricles develop with reduced absorption of continuously secreted CSF. Although the primary disturbance in CSF circulation can remain incurable, its palliation by valve-regulated CSF diversions or shunting can restore normal brain function and in infants permit normal brain development. Missing this goal can result from failure to maintain a sufficiently normal pattern of CSF dynamics and ICP. Monitoring of the CSF pressure fluctuations transmitted through an intraventricular catheter provides the most accurate record of ICP pulsations. Therefore, a pressure sensing module can be “T'd” into an existing shunt system in continuity with the already placed ventricular tube. The capacity to monitor ICP accurately by telemetry was first established in dogs made hydrocephalic to assure free CSF pulse through a ventricular catheter (1,2,3, 4,5). The subsequent use of ICP monitoring by telemetry in three patients will be described.     

Simultaneous measurements of temperature and pH in vivo using NMR in conjunction with TmDOTP5-

NMR techniques for temperature and pH measurements have attracted increasing interest in recent years, motivated in part by the growing importance of medical hyperthermia for the treatment of cancer. The chemical shifts of thulium 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetrakis(methylene phosphonate) (TmDOTP5-) have been studied as a function of temperature and pH. The results demonstrate that TmDOTP5- resonance shifts are highly sensitive to temperature (approximately 1.0 ppm/degrees C) and pH (approximately 3.2 ppm/pH unit) at clinically relevant field strengths. A new method is presented which utilizes two magnetically non-equivalent protons in TmDOTP5- for simultaneous NMR measurements of both temperature and pH. The difference in the chemical shift values of pairs of 1H resonances provides a temperature sensitivity of about 1.6 ppm/ degrees C. The technique is demonstrated in live rats undergoing ultrasound-induced hyperthermia therapy.     

Special behavioral paradigms in animals to study age-related changes in memory

Animal models are important to understand age-related changes in humans. However, the models do not always agree about the effects of aging on memory, and some of the results with animals are different from those with humans. Points of similarity and difference are discussed, indicating some directions for future research.