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Severed body parts, from fingers to extremities, are now being routinely reattached at medical centers around the world. The dream of replantation traces its rich history from miracles and legends to early laboratory experiments and clinical attempts, culminating in today's commonplace procedure.

Purpose: Long-term survival after whole brain irradiation for cerebral metastases is rare. In order to identify a possible subgroup of patients with a prolonged survival time, a retrospective analysis was carried out., Patients and Methods: From 1977 to 1991, 197 patients with singular (51%) or multiple (49%) brain metastases were treated with whole brain irradiation (30 to 36 Gy, 2 to 3 Gy daily fractions, an additional boost of 8 to 20 Gy in 8%) or resection of a singular metastasis and postoperative irradiation (36 patients, 30 to 36 Gy, 2 to 3 Gy fractions whole brain irradiation, boost of 8 to 20 Gy in 31%)., Results: Fifty-seven patients (24%) had metastases of breast cancer. In this group, 3 of 8 patients with combined treatment of a singular metastasis survived more than 5 years from the onset of brain irradiation, compared to 1 of 8 patients with non-small-cell lung cancer and none of 14 patients with unknown primaries. In the group which was treated with irradiation only, breast cancer patients with an interval of more than 5 years between primary and brain metastasis had the best prognosis with 4 of 12 patients surviving more than 3 years, but less than 5 years., Conclusion: These results demonstrate that long-term survival is not only possible in the known cases of solitary brain metastasis in non-small-cell lung cancer but also in breast cancer, combined treatment provided.

Purpose: A 3-dimensional computer simulation was developed in order to estimate the impact of tumor shrinkage on reoxygenation of chronic hypoxic tumor cells during a full course of fractionated irradiation., Material and Methods: The growth of a small tumor situated in a vascularized stroma with 350 capillary cross-sections/mm3 which were displaced by the growing tumor was simulated. Tumors contained 10(4) cells when irradiation started, intrinsic radiosensitivity was set to either low (alpha = 0.3 Gy-1, beta = 0.03 Gy-2) or high (alpha = 0.4 Gy-1, beta = 0.04 Gy-2) values. Oxygen enhancement ratio was 3.0, potential tumor doubling time Tpot = 1.2 or 5 days. A simulated fractionated radiotherapy was carried out with daily fractions of 2.0 Gy, total dose 50 to 70 Gy. The presence or absence of factors preventing tumor cord shrinkage was also included., Results: During the growth phase, all tumors developed a necrotic core with a hypoxic cell fraction of 25% under these conditions. During irradiation, the slower growing tumors (Tpot = 2 to 5 days) showed complete reoxygenation of the hypoxic cells after 30 to 40 Gy independent from radiosensitivity, undisturbed tumor shrinkage provided. If shrinkage was prevented, the hypoxic fraction rose to 100% after 30 to 50 Gy. Local tumor control, defined as the destruction of all clonogenic and hypoxic tumor cells increased by 20 to 100% due to reoxygenation and 50 Gy were enough in order to sterilize the tumors in these cases. In the fast growing tumors (Tpot = 1 day), reoxygenation was only observed in the case of high radiosensitivity and undisturbed tumor shrinkage. In these tumors reoxygenation increased the control rates by up to 60%., Conclusion: The simulation results suggests that shrinking of a homogeneous tumor during irradiation with restoration of the normal vascular architecture can contribute significantly to reoxygenation, which in turn has a major effect on tumor control.

We performed a prospective study of the results of treatment of primary cutaneous melanoma of the foot in 282 patients to determine if there were any factors that could predict survival. These patients were part of a group of 1018 patients who had primary cutaneous melanoma affecting the lower extremity. We found that 184 (65 per cent) of the 282 patients had a tumor that extended into the reticular dermis or subcutaneous tissue (a Level-IV or V lesion according to the system of Clark et al.). Sixty-three patients (22 per cent) had evidence of local, regional, or distant metastatic disease at the time of presentation. Location of the melanoma on the plantar aspect of the foot was found to be an independent variable that was associated with a poorer rate of survival (56 per cent at five years and 46 per cent at ten years) compared with a dorsally located melanoma (80 per cent at five years and 67 per cent at ten years). Subungual lesions were associated with an extremely low rate of survival (17 per cent at ten years); however, because of the small number of subungual lesions that were followed, the difference in survival between the patients who had a plantar lesion and those who had a subungual lesion was not significant (p = 0.52). Variables, in order of decreasing importance, that had independent prognostic significance for survival of patients who had a melanoma of the foot were the clinical stage of the lesion at the time of presentation (p < 0.001) and the age of the patient (p < 0.03), as determined by multivariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

The S100 protein CP-10 (chemotactic protein, 10 kD), a potent chemotactic factor for murine and human polymorphonuclear cells (PMN) and murine monocytes, has been purified in small amounts from supernatants of activated murine spleen cells (Lackmann et al., 1992). To obtain a more abundant source of the protein, CP-10 was expressed in Escherichia coli as a fusion protein with glutathione S-transferase (GST). The property of S100 proteins to undergo calcium-dependent conformational changes was used in a novel approach to optimize the release of recombinant (r) CP-10 by thrombin cleavage. Purified rCP-10 was characterized by amino-terminal sequence analysis and bioassays. Optimal chemotactic activity of rCP-10 for murine PMN and WEHI-265 monocytoid cells was 10(-11) M (native protein has optimal chemotactic activity between 10(-11) and 10(-13) M). Immunization of rabbits with the GST/CP-10 fusion protein bound to glutathione-agarose beads resulted in high titer, specific antibodies that neutralized CP-10-initiated chemotaxis and were suitable for immunoblotting. A combination of Western and Northern analyses identified CP-10 in murine peritoneal exudate PMN and macrophages, splenocytes, bone marrow cells, and WEHI-265 cells (all of myeloid origin), but not in thymus, liver, lung, 3T3 fibroblasts, EL4 lymphoma cells, or bEND 3 brain endothelial cells, indicating cell-specific regulation of CP-10 expression.

Harvesting the central third of the patellar tendon for autograft anterior cruciate ligament reconstruction is thought to compromise quadriceps strength and functional capacity. We compared objective measurements of quadriceps strength and functional capacity in athletes after patellar tendon autograft or allograft anterior cruciate ligament reconstruction. We looked at 33 active male patients (mean age, 24.3 years) who had anterior cruciate ligament reconstructions 12 to 24 months earlier using patellar tendon autograft (N = 15) or allograft (N = 18) techniques. All patients underwent an intensive rehabilitation program. Quadriceps strength and power were assessed by measuring peak torque at 60 and 240 deg/sec, torque acceleration energy at 240 deg/sec, and the quadriceps index using a Cybex II isokinetic testing device. Functional capacity was evaluated based on the results of 3 specially designed functional performance tests and the hop test. Results revealed no significant difference between autograft and allograft groups with respect to any of these parameters. These findings indicate that harvesting the central third of the patellar tendon for autograft anterior cruciate ligament reconstruction does not diminish quadriceps strength or functional capacity in highly active patients who have intensive rehabilitation. Thus, the recommendation to avoid patellar tendon autograft anterior cruciate ligament reconstruction to preserve quadriceps strength and functional capacity may be unnecessary.

The present investigation revealed the presence of lipocortins I and IV, but not lipocortins II and VI, in human platelets. Lipocortin I was found in the Triton-soluble fraction of both resting and thrombin-activated platelets and was not covalently bound to skeletal components. Without detergents, when resting platelets were lysed and fractionated in the absence of Ca2+, lipocortin I was found only in the cytosolic fraction, whereas, in the presence of Ca2+, lipocortin I was associated only with the crude particulate and not with the membrane nor the cytosolic fractions.

Although the importance of protein kinases in platelet activation, particularly protein kinase C (PKC), is well established there remain many problems regarding the various phosphorylation cascades, the role of phosphatases and the importance of other serine/threonine and tyrosine kinases. A particular problem is the mechanism of activation of the fibrinogen receptor, GPIIb/IIIa, a critical step in aggregation. Although GPIIIa is phosphorylated (on threonine) neither the stoichiometry nor the minor changes on activation seem adequate to explain the response. Relatively unspecific inhibitors of PKC such as staurosporine prevent PO4 incorporation into most kinase substrates but only inhibit platelet aggregation partially. However, staurosporine does induce activation and then inhibits several renaturable serine/threonine kinases, probably via phosphatases. Staurosporine did not, however, inhibit the platelet Ca2+ signal in response to thrombin but rather enhanced it. 17-Hydroxywortmannin (HWT), a fungal metabolite, has been shown to inhibit respiratory burst in neutrophils and causes haemorrhages. It was recently reported to be a myosin light chain kinase (MLCK) inhibitor and to inhibit PKC only at much higher concentrations. In platelets, HWT inhibits aggregation and partially inhibits phosphorylation of myosin light chain and P47 in thrombin-activated platelets. It also allows the discrimination of an early and a late phase in the cytoplasmic Ca2+ signal since at lower concentrations it only inhibits the late phase. The late phase of ATP release was also inhibited in a dose-dependent manner. The activation of most of the renaturable serine/threonine kinases was also inhibited by HWT. These results support earlier conclusions that the early phase of the Ca2+ signal is phospholipase C dependent but indicate that other mechanisms must be responsible for the late phase. The relative specificity of HWT for MLCK might indicate that this has an unexpected major role in controlling these late phase reactions including activation of GPIIb/IIIa or its clustering. However, staurosporine completely inhibits phosphorylation of myosin light chain by its kinase (as well as other kinases) and has the opposite effect on Ca2+ signals. Clearly, the interactions and feed-back mechanisms between these kinases are very complex but the results suggest that phosphatases acting together with their complementary kinases should also be considered as important platelet activation regulators. P47, long considered a major PKC substrate, may also be phosphorylated by MLCK.

EEG and somatosensory evoked potentials were recorded in anesthetized rats before and up to 24 h after 30 min of global forebrain ischemia. Before ischemia, SEP (sweep time 1000 ms) included primary (N25P50) components and late potentials of low amplitude. During ischemia, SEP and EEG were isoelectric. During postischemic recirculation SEP evoked by stimulation at 1.0 Hz remained severely suppressed for 24 h, although long-latency potentials (> 100 ms) recovered. Using a very low stimulation frequency of 0.1 Hz, late components strongly increased in amplitude and the overall evoked activity in the averaged post-stimulus-EEG reached 90% of control. These results demonstrate that the SEP evoked at very low stimulation frequency may serve as an early indicator of functional brain recovery after prolonged cerebro-circulatory arrest.

The rate of leucine incorporation into brain proteins was studied in rats with experimental brain tumors produced by intracerebral transplantation of the glioma clone F98. Incorporation was measured with [14C]leucine using a controlled infusion technique for maintaining constant specific activity of [14C]leucine in plasma, followed by quantitative autoradiography and biochemical tissue analysis. After 45 min the specific activity of free [14C]leucine in plasma was 2.5-3 times higher than in brain and brain tumor, indicating that the precursor pool for protein synthesis was fueled both by exogenous (plasma-derived) and endogenous (proteolysis-derived) amino acids. Endogenous recycling of amino acids amounted to 73% of total free leucine pool in brain tumors and to 60-70% in normal brain. Taking endogenous amino acid recycling into account, leucine incorporation was 78.7 +/- 16.0 nmol/g of tissue/min in brain tumor, and 17.2 +/- 4.2 and 9.7 +/- 3.3 nmol/g/min in normal frontal cortex and striatum, respectively. Leucine incorporation within tumor tissue was markedly heterogeneous, depending on the local pattern of tumor proliferation and necrosis. Our results demonstrate that quantitative measurement of leucine incorporation into brain proteins requires estimation of recycling of amino acids derived from proteolysis and, in consequence, biochemical determination of the free amino acid precursor pool in tissue samples. With the present approach such measurements are possible and provide the quantitative basis for the evaluation of therapeutic interventions.

1631 patients with cholelithiasis were operated on between 1984 and 1989 at the St. Clara Hospital in Basel. Mortality and rate of reinterventions were evaluated. 1357 patients had cholecystectomy with a mortality of 0.07%, 217 patients needed an exploration of the common bile duct, which increased the mortality rate to 0.9%. 57 patients had a transduodenal papillotomy, biliodigestive anastomosis or a reoperation without any death. The overall mortality was 0.18%. The mortality for patients over 60 years was 0.4%, there were no deaths for patients under 60 years. The mortality did not increase when there was an acute inflammation of the gallbladder. Reinterventions had to be done in 1.3%. The most common reason for reoperation was a retained common duct stone, which was then removed by endoscopic sphincterotomy (0.86%). Operative injury of the common duct occurred in 0.6% (1 of 1631 patients). Cholecystectomy is still standard treatment of cholelithiasis because of its low mortality and reintervention rate.

Protein kinases are involved in signal transduction in human blood platelets. A number of renaturable protein kinases have increased in vitro activities compared to controls due to covalent modifications when intact platelets are activated by thrombin. The effect of the platelet inhibitor 17-hydroxywortmannin (HWT) on these protein kinases was investigated in intact platelets and in vitro. HWT inhibits the increase in activity of these protein kinases but it does not interact directly with their catalytic subunits. We conclude that HWT blocks a step in signal transduction which is necessary to activate these protein kinases via covalent modifications.

The effects of staurosporine on a selection of protein kinases were investigated with thrombin-stimulated and control human blood platelets. The results demonstrate that staurosporine (1 microM) can lead to activation of certain protein kinases in intact platelets and has a general inhibitory effect on the renaturable protein kinases in vitro. New candidates for protein kinases involved in signal transduction are identified.

Twenty-two para- and tetraplegic patients with chronic spinal cord injuries were examined with magnetic resonance imaging (MRI). The clinical course in the entire rehabilitation period was recorded and an attempt was made to associate the functional status of the patients with the morphologic findings on MRI. Small and large spinal cord cysts and syringomyelia, cord atrophy, and spinal stenosis were found. Additionally, in a number of patients regions of increased signal intensity within the cord, interpreted as myelomalacia, and obliteration of the intradural extramedullary space, interpreted as arachnopathy, were noted. The large number (13/22) of cystic lesions in our patients was unexpected. It was in contrast to the rate reported in autopsy studies of paraplegics which note only few cysts. Whereas a direct association of morphologic findings with neurologic symptoms and the clinical course was difficult, it was found that patients with large cysts and spinal cord atrophy generally showed no tendency to improve in spite of the measures taken during the rehabilitation period. It is difficult to decide whether the initial trauma with cord hemorrhage is limiting the chance of neurological improvement or if a sequence of events leading from hemorrhage to gliosis and cystic necrosis is the determining factor.

Following transient ischemia of the brain, the coupling between somatosensory activation and the hemodynamic-metabolic response is abolished for a certain period despite the partial recovery of somatosensory evoked responses. To determine whether this disturbance is due to alterations of the stimulus-induced neuronal excitation or to a breakdown of the coupling mechanisms, cortical spreading depression was used as a metabolic stimulus in rats before and after ischemia. Adult rats were subjected to 30 min of global forebrain ischemia and 3-6 h of recirculation. EEG, cortical direct current (DC) potential, and laser-Doppler flow were continuously recorded. Local CBF (LCBF), local CMRglc (LCMRglc), regional tissue contents of ATP, glucose, and lactate, and regional pH were determined by quantitative autoradiography, substrate-induced bioluminescence, and fluorometry. Amplitude and frequency of the DC shifts did not differ between groups. In control animals, spreading depression induced a 77% rise in cortical glucose consumption, a 66% rise in lactate content, and a drop in tissue pH of 0.3 unit. ATP and glucose contents were not depleted. During the passage of DC shifts, transient increases (less than 2 min) in laser-Doppler flow were observed, followed by a post-spreading depression hypoperfusion. A comparable although less expressed pattern of hemodynamic and metabolic changes was observed in the postischemic rats. Although baseline LCMRglc was depressed after ischemia, it was activated 47% during spreading depression. Lactate increased by 26%, pH decreased by 0.3 unit, and ATP and glucose remained unchanged. The extent of the transient increase in laser-Doppler flow did not differ from that of the control group, and a post-spreading depression hypoperfusion was also found.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversible cerebral ischemia was produced in rats by occluding both vertebral and both carotid arteries. Following 30 min of ischemia, brains were recirculated for 24 h. The hippocampus, the striatum, and the cortex were sampled, homogenized, and fractionated on a discontinuous sucrose gradient. The fractions were evaluated morphologically by electron microscopy and biochemically by measuring the activity of marker enzymes. Putrescine was extracted from the isolated fractions and measured quantitatively using HPLC and a fluorescence detector. In the total tissue homogenate of control animals putrescine content amounted to 72.0 +/- 3.1, 70.2 +/- 7.6, and 72.7 +/- 2.1 pmol/mg protein in samples prepared from the cortex, the hippocampus, and the striatum, respectively. In the mitochondrial fraction the content was lower, while in the synaptosomal fraction and in myelin it was higher than that in total tissue homogenate. Following cerebral ischemia there was a 6- to 10-fold increase in putrescine in tissue homogenate: In the cortex it increased to 429 +/- 24 pmol/mg protein, in the hippocampus to 585 +/- 70 pmol/mg protein, and in the striatum to 718 +/- 98 pmol/mg protein. Among the isolated fractions the highest levels of putrescine were found in synaptosomes from the striatum (663 +/- 196 pmol/mg protein), followed by the hippocampus (500 +/- 125 pmol/mg protein) and the cerebral cortex (349 +/- 45 pmol/mg protein). This order correlated to the degree of morphological injury which was most pronounced in the striatum and the hippocampus and less in the cerebral cortex. The results of the present study provide further evidence of a relationship between postischemic putrescine levels and the extent of ischemia-induced neuronal injury.

In the experimental F98 rat glioma model the nuclear magnetic resonance contrast agent MnTPPS was used to increase the contrast between tumour and peritumourous brain tissue. By evaluating pre- and postcontrast CPMG echo trains after different dose and circulation times of MnTPPS, the transverse relaxation time T2, the magnetization extrapolated to the time zero M (0), and the contrast ratio Rc of the magnetizations in neoplastic and normal tissues were determined. According to these data a maximum contrast is obtained a few hours after injection of 0.25 mmol MnTPPS/kg bw, using spin echo pulse sequences with short repetition times TR (1,100 ms), and short spin echo time TE (25 ms).

The effect of manganese(III)tetraphenylporphine sulfonate (MnTPPS) on the relaxation enhancement of NMR images (MRI) was studied in experimental brain tumors in rats. Brains were inoculated with the glioma cell line F98 12 to 19 days before the NMR experiment, and the effect of MnTPPS (0.25 mmol/kg body weight) was investigated 2 and 4 days after intraperitoneal injection. After MnTPPS addition tumors could be clearly distinguished by the brightness from the surrounding brain whereas they were barely visible without contrast enhancement. At SE time of 25 msec and TR time of 3500 msec the ratio of magnetization values of tumor versus normal grey matter increased from 0.98 +/- 0.08 to 1.24 +/- 0.09 (means +/- SD). When TR was shortened to 1100 msec contrast enhancement further increased to 1.77 +/- 0.25. These results demonstrate for the first time that MnTPPS is an efficient agent for contrast enhancement of brain tumors.