Psychosis in a primary hyperparathyroidism patient with mild hypercalcemia: A case report.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone (PTH). PHPT presents with a complex set of renal, skeletal, and neuropsychological symptoms. Parathyroidectomy (PTX) is a radical treatment that is recommended for all physically symptomatic patients with PHPT. However, psychiatric symptoms are not considered as an indication for surgery. There remains an important issue from the view of perioperative management of whether PTX should be performed with the presence of uncontrolled psychiatric symptoms or deferred until severe psychiatric symptoms have been controlled. We report a case of mild hypercalcemia that caused severe psychosis in PHPT, which improved dramatically following PTX and resulted in successful postoperative management. PATIENT CONCERN: Our patient was a 68-year-old Japanese woman. She was diagnosed with PHPT, which was triggered by mild hypercalcemia. She was due to receive an operation for osteoporosis and kidney stones. She had severe psychosis, despite medication. Blood examinations revealed mild hypercalcemia (10.4 mg/dL, 8.8-10.1 mg/dL) and elevated serum levels of intact PTH (184.0 pg/mL, 10-65 pg/mL). DIAGNOSIS: She was diagnosed with severe psychosis caused by mild hypercalcemia in PHPT. INTERVENTIONS: Although she was treated with 37.5 mg quetiapine and 2 mg risperidone daily, she was excessively sedated and rejected oral treatment. Therefore, we decided to perform the operation. OUTCOMES: Immediately following surgery, serum levels of calcium, and intact PTH were normalized. Her psychotic symptoms ceased completely 5 days after surgery. CONCLUSION: We emphasize that PHPT presents with various severe psychiatric symptoms, even in mild hypercalcemia. Psychiatric symptoms may be the only salient symptoms in PHPT, and thus clinicians should suspect PHPT in patients with psychiatric symptoms and mild hypercalcemia. Furthermore, PTX is recommended for PHPT-even in the presence of severe uncontrolled psychiatric symptoms, which carries risks for postoperative management-because psychiatric symptoms are expected to improve and good postoperative management is possible.

In situ tissue engineering of the cricoid and trachea in a canine model.

OBJECTIVES: The purpose of the current study was to demonstrate the efficacy of in situ tissue engineering of the cricoid and trachea in a canine model. METHODS: Marlex mesh tube reinforced with polypropylene threads and covered by collagen sponge was used as a tissue scaffold for airway regeneration in 9 beagle dogs. The anterior half of the cricoid cartilage was resected in 5 dogs, whereas the cricoid cartilage and cervical trachea were simultaneously resected in 4 dogs. The tissue scaffold was implanted into the resultant defect. RESULTS: Endoscopic examination showed no airway obstruction for a postoperative period of 3 to 40 months in all dogs. Granulation tissue was observed in 2 dogs, and slight mesh exposure in 1 dog, although all were asymptomatic. Light microscopy and electron microscopy showed the endolaryngeal and endotracheal lumen to be covered by ciliated epithelium. According to strain-force measurement, the framework was firmly supported by regenerated tissue, as well as the normal cricoid and trachea. CONCLUSIONS: Our current tissue scaffold provides a rigid framework for the airway, and the collagen coating invites tissue regrowth around the tube. This study presents the possibility of successful reconstruction of the cricoid and trachea with epithelial regeneration by means of in situ tissue engineering.

Effect of hyperosmolality and cations on iodinated contrast medium-induced potassium release from human blood cells.

PURPOSE: Potassium release from blood cells is a contrast medium-induced phenomenon. The purposes of the study were to (1) assess the effect of hyperosmolality and of adding sodium ions and calcium ions to a solution on potassium release from human blood cells and (2) reevaluate the possibility of hemolysis as a cause of potassium elevation. MATERIALS AND METHODS: Fresh human blood was mixed with a test solution to examine the temporal changes in the whole blood potassium levels and to calculate the potassium release rate. Test solutions included 5%, 20%, and 50% glucose; 0.9% and 10% NaCl; and 50% glucose mixed with various amounts of sodium and calcium ions. We also measured serum glutamine oxaloacetic acid transaminase (GOT) and serum lactate dehydrogenase (LDH) to evaluate the possibility of hemolysis. RESULTS: Hyperosmolality using glucose solutions promoted higher potassium release. The average +/- SD potassium release rates were 7.3 +/- 2.4 micromol/min with 5% glucose, 13.5 +/- 2.3 micromol/min with 20% glucose, and 128.4 +/- 44.9 micromol/min with 50% glucose. The solutions including sodium ions showed lower release rates. The addition of sodium and calcium ions into 50% glucose significantly lowered the potassium release rates. No significant elevation of GOT or LDH was observed, and the possibility of hemolysis was eliminated. CONCLUSION: Hyperosmolar glucose solution promoted potassium release, but the presence of sodium ions in the hypertonic solution inhibited it. In addition, there is no possibility of hemolysis as a cause of potassium release.

Fibroblast growth factor-2 promotes recovery of pulmonary function in a canine models of elastase-induced emphysema.

Bronchoscopic lung volume reduction (BLVR) for severe emphysema is less invasive than lung volume reduction surgery. Fibroblast growth factor-2 (FGF-2) has been reported to enhance fibrogenesis and angiogenesis. The aim of this study was to investigate the feasibility of BLVR with the FGF-2, and ability to reduce lung volume and promote recovery of lung function. The BLVR based on FGF-2 is less invasive than surgical procedures, and can be performed repeatedly if the effectiveness of volume reduction is inadequate. This simple bronchoscopic approach allows selective reduction in the volume of the emphysematous parenchyma, and intratracheal administration of FGF-2 induces an increase in pulmonary blood flow, thus allowing recovery of pulmonary function.

Development of beta-tricalcium phosphate/collagen sponge composite for bone regeneration.

Synthetic biomaterials have been developed and used for bone grafting. Here, we developed a biodegradable sponge composite for bone tissue engineering by combining beta-tricalcium phosphate (beta-TCP) and collagen. In addition, we sought to determine the optimal beta-TCP granules/collagen ratio by evaluating and bone formation in vivo. Porous beta-TCP granules were mixed with atelocollagen hydrochloride solution at various ratios--0.02, 0.05, 0.1, and 0.2 g/mL. The resultant mixtures were freeze-dried and subjected to dehydrothermal treatment in vacuo. The final composites obtained were designated beta-TCP/collagen sponge composites (beta-TCP/CS). Through compression testing, it was found that the stress values for beta-TCP/CS (0.2 g/mL) were higher than those of the other three composites over the whole strain range. Histological evaluation at four weeks after implantation revealed that the collagen sponge had degraded and newly formed bone was present on the surface of the beta-TCP granules. At 12 weeks, the beta-TCP granules were completely degraded and remodeling of the lamellar bone was observed.

Tissue engineering of small intestinal tissue using collagen sponge scaffolds seeded with smooth muscle cells.

In a previously reported attempt to regenerate small intestine with autologous tissues, collagen scaffolds were used without cell seeding or with autologous mesenchymal stem cell seeding. However the regenerated intestine lacked a smooth muscle layer. To accomplish regeneration of a smooth muscle layer, this present study used collagen scaffolds seeded with the smooth muscle cells (SMC) in a canine model. Autologous SMC were isolated from stomach wall and cultured. Two types of scaffolds were fabricated: in SMC (+), cultured SMCs were mixed with collagen solution and poured into a collagen sponge; and in SMC (-), SMCs were omitted. Both scaffolds were implanted into defects of isolated ileum as a patch graft. Animals were euthanized at 4, 8, and 12 weeks; for the last time point, the ileal loop had been reanastomosed at 8 weeks. At 12 weeks, the SMC (-) group showed a luminal surface covered by a regenerated epithelial cell layer with very short villi; however only a thin smooth muscle layer was observed, representing the muscularis mucosae. In the SMC (+) group, the luminal surface was covered completely by a relatively well-developed epithelial layer with numerous villi. Implanted SMCs were seen in the lamina propria and formed a smooth muscle layer. Thus, we concluded that collagen sponge scaffolds seeded with autologous SMCs have a potential for small intestine regeneration.

Fibroblast growth factor-2 induces recovery of pulmonary blood flow in canine emphysema models.

STUDY OBJECTIVES: Fibroblast growth factor (FGF)-2 is one of the most powerful angiogenic growth factors to be evaluated as an agent for the promotion of angiogenesis. The aim of this study is to investigate whether intratracheal administration of controlled-release FGF-2 microspheres restores pulmonary function in beagle dogs with emphysema. DESIGN: Randomized, controlled, experimental animal study. SUBJECTS: Eighteen Wister rats and 15 adult beagle dogs. METHODS: In the rat study, we compared the time profiles of the radioactivity remaining after intratracheal injection of 125I-labeled FGF-2, either incorporated with the controlled-release microspheres or as an aqueous solution. In the dog study, elastase-induced emphysema models were developed in 10 animals, classified into the following three groups: control group (n = 5), emphysema model with empty microspheres-treated group (FGF - group, n = 5), and emphysema model with FGF-2 containing microspheres-treated group (FGF + group, n = 5). RESULTS: In the rat study, controlled-release microspheres maintained higher whole-lung FGF-2 concentrations after intratracheal administration. In the dog study, Pa(O2) in the FGF + group was significantly higher than in the FGF - group after treatment. Pulmonary perfusion dynamic MRI revealed significant improvement in the signal intensity of damaged lung with the FGF + group. Linear intercept of the FGF + group was significantly reduced than the FGF - group. CONCLUSION: Results indicate that intratracheal administration of FGF-2 induced an increase in pulmonary blood flow in the damaged lung and led to recovery of pulmonary function. The controlled-release microsphere system increased the effectiveness of FGF-2.

Regenerative medicine of the trachea: the first human case.

OBJECTIVES: The objective of the present study was to demonstrate regenerative medicine of the tracheal tissue by using an in situ tissue engineering technique for airway reconstruction. METHODS: Based on the previous successful experimental animal studies, the current regenerative technique was applied to repair of the trachea of a 78-year-old woman with thyroid cancer. A Marlex mesh tube covered by collagen sponge was used as a tissue scaffold. The operative intervention included right hemithyroidectomy, resection of the trachea, and tracheoplasty using the scaffold. The right half of three rings of the trachea was resected, and the scaffold material was sutured to the defect of the trachea. RESULTS: After 2 weeks, the mesh collagen structure of the artificial material could be seen with endoscopy in most of the implanted area. The artificial material was covered with epithelial growth after 2 months. Epithelialization continued to cover the artificial material completely for 2 years without any complications. CONCLUSIONS: The current regenerative technique avoided tracheotomy, a second operation, and deformity. Good epithelialization has been observed on the tracheal luminal surface without any complications for 2 years. Although long-term observation is required, regenerative medicine of the tracheal tissue appears feasible for airway reconstruction.

An experimental model of Stanford type B aortic dissection.

PURPOSE: To create an experimental model of aortic dissection with a long-lasting patent false lumen as a proper animal model for development of less-invasive treatment for aortic dissection. MATERIALS AND METHODS: Fifteen adult beagle dogs (weight, 10-12 kg) were used. The descending aorta was exposed by a left thoracotomy at the sixth intercostal space. The entry for the aortic dissection was created surgically just distal to the origin of the left innominate artery and the reentry was 5 cm distal to the entry point. Normal saline solution was injected into the aortic wall (ie, media) between these two points to create the dissection. The dogs were followed up at 1 day, 3 months, 1 year, and 2 years. RESULTS: All 12 surviving dogs had completely patent true and false lumina without any thrombi. Microscopic examination showed that the dissection was created in the tunica media layer, making it identical to aortic dissection in humans. Color Doppler imaging confirmed the patency of the true and false lumina and the relatively narrowed true lumen. CONCLUSION: In this canine model of aortic dissection, the false lumen has excellent long-term patency and the dissection plane is histologically similar to that in human aortic dissection. This model may contribute to the development of new treatments for Stanford type B aortic dissection.

New canine spinal cord injury model free from laminectomy.

The present report details the successful development of a model for spinal cord injury (SCI). This model is simple, reproducible, and requires no laminectomy. Development of the model was carried out using fourteen dogs. A balloon catheter was inserted into the extradural space via the intervertebral foramen of each dog, then the balloon was inflated at the L1 level by injection of saline. Six dogs underwent compression with a balloon volume of 1.5 ml, three dogs with a volume of 1.0 ml, and the remaining five dogs were used as uninjured controls. We applied the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale to the dogs. Compression of the spinal cord for 10 min at 1.5 ml produced severe paraplegia (BBB remained zero or one for 6 months following surgery), while compression for the same time interval at 1.0 ml produced moderate paraplegia. Electrophysiological tests showed no hindlimb movement upon stimulation cranial to the site of injury in the 1.5-ml group. The volume of abnormal-intensity lesions in the 1.0-ml group calculated using MR imaging showed no marked changes in either high- or low-intensity lesions after 3 months, whereas in the 1.5-ml group, the low-intensity lesions alone showed a marked increase. Pathological examination of the damaged spinal cord showed the formation of cavities surrounded by scar tissue containing high levels of collagen. These findings closely resembled those of clinical cases. It was concluded that 10 min of balloon compression with a volume of 1.5 ml caused irreversible paraplegia in dogs.

Calcium binding by gadolinium-based MR contrast agents.

PURPOSE: This study was conducted to characterize the alterations in ionic sodium, potassium, and calcium by gadolinium-based MR contrast agents. MATERIALS AND METHODS: An electrolyte solution (ES) containing 1.2 mM/L calcium ions,120 mM/L sodium, and 4.0 mM/L potassium were diluted with various gadolinium compounds and alterations in ionized electrolytes were measured using an ion-specific electrometer. Gadolinium compounds including Gd-DTPA, Gd-DOTA, gadoteridol, gadodiamide, meglumine/sodium diatrizoate (76% Urografin), and isotonic saline as a control were investigated. The dilution ranged from 5% (ES/test solution = 100/5) to 100%. Alterations of ionic electrolytes were measured. Calcium-binding capacities caused by each gadolinium compound also were measured. RESULTS: The alterations of ionic sodium and potassium by gadolinium compound were similar to those of isotonic saline. A significant reduction in ionized calcium was observed with Gd-DTPA and Gd-DOTA in comparison with gadoteridol and gadodiamide. CONCLUSION: Ionic gadolinium compounds induced significant reductions of calcium ions in vitro compared with non-ionic gadolinium compounds.

Experimental study on the regeneration of peripheral nerve gaps through a polyglycolic acid-collagen (PGA-collagen) tube.

We have developed a bioabsorbable polyglycolic acid (PGA) tube filled with collagen sponge (PGA-collagen tube) as a nerve connective guide, and compared its effectiveness with that of autograft in terms of nerve regeneration across a gap. The PGA-collagen tube was implanted into 24 beagle dogs across a 15-mm gap in the left peroneal nerve. The right peroneal nerve was reconstructed with the autograft harvested from the left side, as a control. After the surgery, the connective tissue extended from both cut ends in the PGA-collagen tube and connected again at the center. Pathologically, the collagen sponge in the tube provided adequate scaffolding for nerve tissue extension, and the nerve tissue reconnected within 3 weeks. Electrophysiologically, muscle-evoked potentials (MEPs) and compound nerve action potentials (CNAPs) were detected 18 days after the surgery. For up to 6 months postsurgery, CNAPs and somatosensory-evoked potentials (SEPs) on the PGA-collagen side had a shorter latency and larger peak voltage than those on the autograft side. The myelinated axons on the PGA side were larger in diameter than those on the autograft side. It is suggested that the PGA-collagen tube has the potential to be an effective alternative to conventional autografting for the repair of some peripheral nerve defects.

Cricoid regeneration using in situ tissue engineering in canine larynx for the treatment of subglottic stenosis.

The purpose of the present study was to evaluate the efficacy of cricoid regeneration via in situ tissue engineering in a canine larynx for the treatment of subglottic stenosis. As the tissue scaffold, a Marlex mesh tube coated by collagen sponge was used for a rigid airway framework and for tissue regrowth around the tube. On 5 dogs, the larynx was exposed and the anterior third of the cricoid cartilage was resected. The tube was anastomosed to the lower edge of the thyroid cartilage and to the first tracheal cartilage. By postoperative endoscopic examination at 3 to 7 months, no airway obstruction was observed in any of the dogs. There was granulation tissue in 2 dogs and slight mesh exposure in 1 dog, but they were asymptomatic. Confluent regeneration of the epithelium over the scaffold and good incorporation of the scaffold mesh into the host tissue were observed after surgery.

Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs.

Primary pulmonary hypertension (PPH) is still a refractory disease, and patients deteriorate despite any treatment. We hypothesized that neovascularization in the lung could increase the volume of the vascular bed in the pulmonary circulation and thus reduce the development of pulmonary hypertension (PH). Endothelial progenitor cells (EPCs) might be a potential cell source for neovascularization. We examined the effects of EPC transplantation into the lungs of dogs with dehydromonocrotaline-induced PH. The lung parenchyma of PH model dogs was injected with ex vivo-expanded, autologous EPCs originated from peripheral blood (experiments, n=4) or culture medium (control, n=3), using a bronchoscope. EPC transplantation gave significant improvements in mean pulmonary artery pressure, cardiac output, and pulmonary vascular resistance. Histological evaluation revealed both improvement in the medial thickness of the small pulmonary artery and neovascularization of the lung tissue. These results indicate that EPC transplantation into the lung is effective at preventing the progression of dehydromonocrotaline-induced PH in dogs, and suggest a new therapeutic option for PPH.

In situ tissue engineering of periodontal tissues by seeding with periodontal ligament-derived cells.

The feasibility of an in situ tissue-engineering method employing cell-based therapy with autologous periodontal ligament-derived cells was investigated. Periodontal ligament cells were obtained from six beagle dogs. Periodontal fenestration defects (6 x 4 mm) were created bilaterally at a location 6 mm apical to the marginal alveolar crest in the maxillary canines. Alkaline phosphatase-positive periodontal ligament cells (3 x 10(5) cells) were seeded onto a collagen sponge scaffold just before implantation. One defect was filled with the cell-scaffold construct, and another was left empty as the control. All animals were killed 4 weeks after surgery, and specimens were evaluated histomorphometrically. All the histomorphometrical data were analyzed by three-way analysis of variance with the Bonferroni multiple comparisons test. Regeneration of apical tissue was faster than that of coronal and isolated tissues on the control side (apical > coronal > isolated; p < 0.0001). On the other hand, on the cell-seeded side, regeneration of the cementum was observed uniformly on the root surface. Our data suggest that the seeded cells induced cementum regeneration on the root surface, indicating the potential of in situ tissue engineering using autologous cells for the regeneration of periodontal tissues.

Tissue engineering for the regeneration of the mastoid air cells: a preliminary in vitro study.

Mastoid is a pneumatic bone, composed of small interconnecting chambers covered by a mono-layer of mucosa with an abundant blood supply. One of its main functions is gas exchange according to the concentration/pressure gradient. The final goal of our research project is to regenerate mastoid air cells and their unique physiologic functions. The aim of the present study is to determine appropriate cultivating conditions for the cells cultured on the surface of artificial hydroxyapatite. In our in vitro experiment, to imitate the skeleton of mastoid bone, we used two types of three-dimensional hydroxyapatite (3D-HA), i.e. with a high (90%) and low (60%) percentage of micropores. The former type was divided into two groups: collagen-coated and non-coated. Canine mucosal- and bone marrow-derived stromal cells (BSCs), from the oral floor and femur respectively, were harvested and cultured on the 3D-HA under different conditions. To estimate the proliferation/distribution of the cultured cells over the surface of the 3D-HA, these cells were stained with the dye DiI and hematoxylin-eosin. There were no significant differences in the proliferation of cultured cells on the 3D-HA with high and low percentages of micropores. Collagen-coated HA was a better material for the cultured cells compared with the non-coated HA. Co-cultured mucosal and BSCs proliferated better than those cultured separately. In conclusion, this tissue engineering technique may be applied for the regeneration of mastoid air cells.

Regeneration of mastoid air cells: clinical applications.

The objective of this study was to establish a method for regenerating mastoid air cells and their functions for clinical use in incurable otitis media. For this clinical study three patients (one male, two female) were randomly selected from patients with severe cholesteatoma about to undergo staged operations. Hydroxy-apatite in three-dimensional, honeycomb-like structures (3D-HA) were used as artificial pneumatic bones. This 3D-HA is made of calcium phosphate and has a high percentage of micropores (90%). Its surface is coated with collagen. At the first stage of tympanoplasty, collagen-coated 3D-HA was put into the opened mastoid cavity and fixed by fibrin glue. Recovery of mastoid aeration and regeneration of the pneumatic air cells of the mastoid cavity were estimated on CT scan images after the first operation. Aeration was recovered in all cases. The mastoid air cells were regenerated in two cases. In the failed case, subcutaneous connective tissues and granulations invaded into the spaces of the 3D-HA. This study demonstrated that mucosa would grow on the surface of a 3D-HA implant and could provide gas exchange functions in the newly opened mastoid cavity. This tissue engineering method may be a possible treatment for intractable otitis media.

Slow release of bone morphogenetic protein 2 from a gelatin sponge to promote regeneration of tracheal cartilage in a canine model.

OBJECTIVES: We investigated whether bone morphogenetic protein 2, released slowly from a gelatin sponge, could induce cartilage regeneration in a canine model of tracheomalacia and evaluated the long-term results. METHODS: A 1 x 5-cm gap was made in the anterior cervical trachea by removing 5-cm long strips of 10 sequential cartilagines. In the control group (n = 5), the gaps were left untreated. In the gelatin sponge group (n = 5), a gelatin sponge soaked in a buffer solution was implanted in each defect. In the bone morphogenetic protein group (n = 5), a gelatin sponge soaked in a buffer solution containing 12 microg bone morphogenetic protein 2 was implanted in each defect. RESULTS: Tracheomalacia was observed in the control and gelatin sponge groups but not in the bone morphogenetic protein group. No regenerated cartilage was detected in the control or gelatin sponge groups, even 6 months after surgery. In contrast, regenerated cartilage, which had developed from the host perichondrium, was observed around the stumps of the resected cartilagines in the bone morphogenetic protein group. This regenerated cartilage maintained the integrity of the internal lumen for longer than 6 months. A compressive fracture test revealed that the tracheal cartilage in the bone morphogenetic protein group was significantly more stable than that in the gelatin sponge and control groups (P =.0015 and P =.0001, respectively). CONCLUSIONS: In this canine model of tracheomalacia, cartilage regeneration was induced around the stumps of tracheal cartilagines by bone morphogenetic protein 2 released slowly from a gelatin sponge. This regenerated cartilage was not reabsorbed for longer than 6 months and was strong enough to maintain the integrity of the internal lumen of the trachea.

Sterilized, freeze-dried amniotic membrane: a useful substrate for ocular surface reconstruction.

PURPOSE: To examine the feasibility of using sterilized, freeze-dried amniotic membrane (FD-AM) as a substrate for cultivating autologous corneal epithelial cells for ocular surface reconstruction. METHODS: Human AM deprived of amniotic epithelial cells by incubation with EDTA was freeze dried, vacuum packed, and sterilized with gamma-irradiation. The resultant FD-AM was characterized for its physical, biological, and morphologic properties by stretch stress tests, immunohistochemistry, electron microscopy, and cell culture. In addition, 3 weeks after an ocular surface injury, the conjunctivalized corneal surfaces of eyes in eight rabbits were surgically reconstructed by transplantation of autologous cultivated corneal epithelial cells on FD-AM. RESULTS: A stretch stress test revealed no significant differences between sterilized FD-AM and cryopreserved AM. Immunohistochemistry for several extracellular matrix molecules and electron microscopic analysis of FD-AM revealed that the process of drying and irradiation did not affect its biological and morphologic properties. The corneal epithelial cells cultivated on FD-AM had four to five stratified, well-differentiated cell layers. Corneas that were grafted with the cultivated corneal epithelial cells on FD-AM were clear and were all epithelialized at 10 days after surgery. CONCLUSIONS: The sterilized, freeze-dried AM retained most of the physical, biological, and morphologic characteristics of cryopreserved AM; consequently, it is a useful biomaterial for ocular surface reconstruction.