Tumor-induced hypercalcemia in a patient with extensive soft tissue sarcoma: Effects of bisphosphonate therapy and surgery

Tumor-induced hypercalcemia (TIH) is a frequent complication of advanced cancer, but it has been rarely reported in patients with sarcoma. We describe the case of a young female patient with TIH and with an extensive synoviosarcoma of the left lower limb destroying the bony structures. Hypercalcemia was severe (18.3 mg/dl) and accompanied by low serum P_i and suppressed parathyroid hormone (PTH) and 1,25(OH)₂ vit D₃ serum concentrations. Hypercalcemia was successfully treated with ibandronate, a new third-generation bisphosphonate, and radical surgery was performed when the patient was normocalcemic. Circulating levels of PTH-related protein (PTHrP) were elevated at 22.5 pmol/L (NI <9) PTHrP levels did not change after successful therapy of TIH, in contrast with PTH, which increased sharply. PTHrP levels were normalized after radical surgery. Moreover, low serum Pi with reduced threshold for phosphate excretion and increased tubular calcium reabsorption supported the notion that PTHrP was indeed the essential mediator of paraneoplastic hypercalcemia in this case despite the extensive bone destruction. © 1996 Wiley-Liss, Inc.     

Differential effects of Bcl-2 overexpression on fibre outgrowth and survival of embryonic dopaminergic neurons in intracerebral transplants

The causes of death of transplanted neurons are not known in detail, but apoptotic mechanisms involving caspase activation are likely to play a role. We examined whether overexpression of the anti-apoptotic protein Bcl-2 may enhance the survival of dopaminergic [tyrosine hydroxylase (TH)-immunoreactive] grafted neurons. For this purpose, we prepared cells from embryonic day 13 ventral mesencephalon (VM) of mice overexpressing human Bcl-2, or from their wild-type littermates. The bcl-2 transgene was strongly expressed in these cells, and resulted in protection of neuronal cultures from death triggered by serum deprivation or exposure to staurosporine. To model pretransplantation stress more closely in vitro, we stored dissociated embryonic mesencephalic cells for 8 h in the same type of medium used for intracerebral transplantation. This resulted in massive cell death as quantified by lactate dehydrogenase (LDH) release, and increased DNA fragmentation. Although this cell loss was strongly reduced by a caspase inhibitor, Bcl-2 had no significant protective effect. Finally, mesencephalic cell suspensions were xenografted into the striatum of immunosuppressed hemiparkinsonian rats. Neither the survival of TH-immunopositive transplanted neurons nor the functional recovery of the rats was improved by Bcl-2, although the Bcl-2 protein was strongly expressed in transgenic grafts 5 weeks after implantation, and dopaminergic fibre outgrowth from the grafts was significantly improved. These data suggest that cell death in neuronal transplants involves apoptotic mechanisms that can bypass negative regulation by Bcl-2.     

Combined use of T1-weighted MRI and MRA for stereotaxic lesioning of the nonhuman primate brain: application to the rhinal cortex

 Stereotaxic brain lesioning is widely used to develop experimental models of human brain disease in the nonhuman primate. To avoid intraoperative vascular complications such as intracranial hemorrhage, we developed a methodology that is easy to implement. This method combines T1-weighted magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). This technique is applied to produce bilateral neurotoxic lesions of the rhinal cortex, a structure located medially in the temporal lobe, in eight baboons (including five sham-operated animals with needle descents but no ibotenic acid injection). Two other baboons were lesioned before the MRA technology was available. The MRA sequence (two-dimensional time-of-flight, axial acquisition) was used to localize the blood vessels in the needle trajectories, i.e., the highly vascularized sylvian fissure and temporal gyri. The vessel coordinates were transposed onto the coronal MRI-T1 images, onto which the injection sites were determined and the planned needle tracks drawn. In the eight baboons that had MRA, 26.8% of these needle tracks had to be slightly displaced because of the presence of blood vessels. The stereotaxic coordinates of the final target sites were then calculated with respect to six skull landmarks that also served as a reference during surgery. No intracranial hemorrhage occurred in any of the eight baboons in which MRA was performed, in contrast to one of the two baboons not studied with MRA. The histological analysis showed a good extent of the rhinal lesions in all lesioned animals, with minimal damage to areas other than those that were targeted. Thus, combined use of MRI-T1 and MRA proved to be reliable in reducing vascular complications, affording new advances for stereotaxic surgery in nonhuman primates. Received: 16 June 1998 / Accepted: 13 November 1998     

Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C

Liver fibrosis is the main predictor of the progression of chronic hepatitis C, and its assessment by liver biopsy (LB) can help determine therapy. However, biopsy is an invasive procedure with several limitations. A new, noninvasive medical device based on transient elastography has been designed to measure liver stiffness. The aim of this study was to investigate the use of liver stiffness measurement (LSM) in the evaluation of liver fibrosis in patients with chronic hepatitis C. We prospectively enrolled 327 patients with chronic hepatitis C in a multicenter study. Patients underwent LB and LSM. METAVIR liver fibrosis stages were assessed on biopsy specimens by 2 pathologists. LSM was performed by transient elastography. Efficiency of LSM and optimal cutoff values for fibrosis stage assessment were determined by a receiver-operating characteristics (ROC) curve analysis and cross-validated by the jack-knife method. LSM was well correlated with fibrosis stage (Kendall correlation coefficient: 0.55; P < .0001). The areas under ROC curves were 0.79 (95% CI, 0.73-0.84) for F > or =2, 0.91 (0.87-0.96) for F > or =3, and 0.97 (0.93-1) for F=4; for larger biopsies, these values were, respectively, 0.81, 0.95, and 0.99. Optimal stiffness cutoff values of 8.7 and 14.5 kPa showed F > or =2 and F=4, respectively. In conclusion, noninvasive assessment of liver stiffness with transient elastography appears as a reliable tool to detect significant fibrosis or cirrhosis in patients with chronic hepatitis C.     

Imaging visual recognition memory network by PET in the baboon: perirhinal cortex heterogeneity and plasticity after perirhinal lesion.

We recently mapped the visual recognition memory network in the behaving baboon using a positron emission tomography (PET) activation paradigm with 18F-fluoro-deoxyglucose during a visual delayed matching-to-sample task. This study confirmed the key role of the perirhinal cortex and documented an unexpected left-sided advantage. Specific contribution of each subdivision of the perirhinal cortex has, however, never been investigated. Furthermore, although alteration to the perirhinal cortex has been implicated in several brain disorders, putative plasticity within the entire brain network after perirhinal damage remains largely unknown. To confirm our previous data and to investigate these latter issues, we used our PET activation paradigm on a second healthy baboon before and after 16 months after bilateral excitotoxic lesions of the perirhinal cortex. Activation common to our two healthy baboons occurred only in the left rostroventral perirhinal cortex (i.e., areas 36pm and rostral 36r) and insular cortex. Although histologic analysis disclosed that the perirhinal lesions achieved in the present baboon were essentially caudal to this preoperatively activated area, memory performance was severely impaired. Concomitant with this long-lasting cognitive deficit, changes in the neural network implicated in the task were observed, involving disappearance of the preoperative activations and appearance of a significant activation of the frontal and occipital cortices. However, different activation patterns were found in the first and last eight postoperative months. These findings highlight the functional heterogeneity of the perirhinal cortex and evidence progressive plasticity after perirhinal cortex damage.     

Worsening of hepatic dysfunction as a consequence of repeated hydroxyethylstarch infusions

BACKGROUND/AIMS: Due to its apparent safety and low cost, hydroxyethylstarch (HES) is increasingly used as a volume expander. The aim of this retrospective study was to highlight the risk of hepatic dysfunction after iterative HES infusions. METHODS: Between April 1996 and April 1998, nine patients were referred for worsening of their clinical condition after repeated HES infusions. Six patients had previous chronic liver disease, cirrhosis in four cases. All patients underwent a liver biopsy. RESULTS: All post-HES liver biopsies showed diffuse microvacuolization of Kupffer cells, which was associated with focal hepatocyte vacuolization in seven cases. The vacuoles contained periodic acid Schiff positive material at their margins and were lysosomal by electron microscopy. The clinical symptoms of hepatic disease, although difficult to interpret in cirrhotic patients, worsened after HES infusions. Portal hypertension was noted in three non-cirrhotic patients. Serum alkaline phosphatase and gammaglutamyl transferase activities were increased when compared with previous values. Eight patients died, six of them within 1-4 weeks of hepatic failure or septic shock. In the only living patient, symptoms improved after HES withdrawal. CONCLUSIONS: Repeated administration of HES could favour severe portal hypertension, liver failure and sepsis, particularly in the setting of chronic liver disease. The basis of these adverse effects is the lysosomal storage of HES in Kupffer cells and hepatocytes.     

Molecular prenatal diagnosis of partial androgen insensitivity syndrome based on the Hind III polymorphism of the androgen receptor gene*

OBJECTIVE Partial androgen Insensitivity syndromes are the cause of genital ambiguity that is at times quite severe; there is, therefore, a high demand for prenatal diagnosis in families already afflicted with this syndrome. When the mutation has not been identified, the diagnosis can be made by the study of the polymorphisms of the androgen receptor gene. To perform molecular prenatal diagnosis in a family with partial androgen insensitivity syndrome, we studied the Hind III polymorphism of the androgen receptor gene on the trophoblastic DNA. The use of this restriction fragment length polymorphism tracked maternal X chromosome segregation and established prenatal diagnosis although the mutation had not yet been identified in this family. FAMILY The mother had been previously described as heterozygous for the Hind III polymorphism and chromosomal segregation analysis showed that the affected allele was associated with the 6.7-kb Hind III fragment. MEASUREMENTS Hind III RFLP with an androgen receptor gene cDNA probe was realized on the trophoblastic DNA, along with measurement of androgen binding activity on the trophoblastic cells. RESULTS We detected the presence of the 6.7-kb fragment In the DNA of the trophoblastic cells suggesting the fetus was affected. Partial androgen insensitivity syndrome was confirmed by a considerable decrease in androgen binding activity on the trophoblastic cells and by sonography of the fetus. After a therapeutic abortion requested by the parents, the diagnosis was confirmed by clinical examination of the fetus, biochemical analyses of the fetal androgen receptor, and molecular studies of the fetal DNA. CONCLUSIONS When the mutation of the androgen receptor gene has not been identified, Hind III polymorphism of the trophoblastic DNA is useful in the prenatal diagnosis of androgen insensitivity syndrome in high-risk families.     

Periodontal tissue regeneration by combined applications of recombinant human osteogenic protein-1 and bone morphogenetic protein-2. A pilot study in Chacma baboons (Papio ursinus)

Native and recombinant human bone morphogenetic/osteogenic proteins (BMPs/ OPs) singly initiate bone induction in vivo. The finding of synchronous but spatially different BMPs/OPs expression during periodontal tissue morphogenesis suggests novel therapeutic approaches using morphogen combinations based on recapitulation of embryonic development. Twelve furcation defects prepared in the first and second mandibular molars of three adult baboons (Papio ursinus) were used to assess whether qualitative histological aspects of periodontal tissue regeneration could be enhanced and tissue morphogenesis modified by combined or single applications of recombinant hOP-1 and hBMP-2. Doses of BMPs/OPs were 100 microg of each protein per 1 g of insoluble collagenous bone matrix as carrier. Approximately 200 mg of carrier matrix was used per furcation defect. Undecalcified sections cut for histological analysis 60 d after healing of hOP-1-treated specimens showed substantial cementogenesis with scattered remnants of the collagenous carrier. hBMP-2 applied alone induced greater amounts of mineralized bone and osteoid when compared to hOP-1 alone or to combined morphogen applications. Combined applications of hOP-1 and hBMP-2 did not enhance alveolar bone regeneration or new attachment formation over and above the single applications of the morphogens. The results of this study, which is the first to attempt to address the structure-activity relationship amongst BMP/OP family members, indicate that tissue morphogenesis induced by hOP-1 and hBMP-2 is qualitatively different when the morphogens are applied singly, with hOP-1 inducing substantial cementogenesis. hBMP-2 treated defects, on the other hand, showed limited cementum formation but a temporal enhancement of alveolar bone regeneration and remodelling. The demonstration of therapeutic mosaicism in periodontal regeneration will require extensive testing of ratios and doses of recombinant morphogen combinations for optimal tissue engineering in clinical contexts.