[Mesenchymal stroma cells and their niche]. / Mesenchymale Stromazellen und ihre Nische.

Stem cells reside in a highly specialized, complex microenvironment that is known as the stem cell niche. The stem cell niche can be described as an anatomically defined space where the stem cell is localized and nourished and stem cell quiescence, proliferation and differentiation are maintained. Tissue engineering aims to imitate the stem cell niche to (I) induce a directed differentiation, (II) maintain the self-renewal capacity or (III) find a regulated balance between self-renewal and differentiation. Mesenchymal stem or stromal cells (MSC) can differentiate in three-dimensional collagen gels into functional osteoblasts when subjected to a phosphate-rich cultivation medium. Furthermore, they acquire a prosynthetic, matrix remodeling, contractile phenotype. Medial artery calcification in patients with chronic kidney disease also proceeds through intramembranous ossification resulting from osteoblast-induced calcification of the collagen extracellular matrix. Thus, the influence of uremic cultivation conditions as a pathophysiological stimulus on MSC and endothelial cells was analyzed with special regards to matrix remodeling, vascularization and calcification. The results showed that BMP-2/4 mediated MSC (mal)differentiation into osteoblasts with acquired matrix remodeling phenotype and loss of proangiogenic capacity. These studies have led to the conclusion that uremia has detrimental effects on the stem cell niche and promotes the continuous calcification by osteogenic (mal)differentiation. In summary, recent studies have shown the conducting and regulating effect of the stem cell niche under physiological conditions that can be applied and mimicked for tissue engineering applications. However, under pathological conditions the stem cell niche can have detrimental effects on stem cell function and can promote disease progression.

[The 'red puffy ear sign'--a clinical sign to diagnose a rare cause of meningoencephalitis]. / Das "red puffy ear sign" - ein klinisches Zeichen zur Diagnose einer seltenen Meningoenzephalitis.

We report on the case of a 63-year-old patient with a meningoencephalitis, presenting itself with headache and a general neuropsychological retardation. Additionally, a reddening and swelling of both auricles could be seen. Magnetic resonance imaging showed confluent, contrast-uptaking lesions. In the cerebrospinal fluid an aseptic lymphocytic pleocytosis was found. A biopsy of the ear revealed a chronic lymphoplasmacellular inflammatory reaction. We diagnosed a relapsing polychrondritis, an inflammatory disease of the cartilage, which can in rare cases affect the central nervous system. Typically, the patients complain about red swollen ears, the "red puffy ear sign". After initiation of steroid and azathioprin therapy the patient recovered fully.

[Mesenchymal stem cells and their interaction with biomaterials: potential applications in tissue engineering]. / Mesenchymale Stammzellen und ihre Interaktionen mit Biomaterialien: Anwendungsmöglichkeiten im Tissue-Engineering.

INTRODUCTION: Mesenchymal stem cells (MSC) are an important cell type for regenerative medicine and tissue engineering. They are involved in tissue regeneration by means of: (a) differentiation into specialised mesodermal cells and (b) their biosynthetic activity that is both immunomodulatory and trophic. In recent studies we analysed MSC in contact with different biomaterials to identify suitable combinations for tissue engineering. METHODS: A biomaterial test platform was established to analyse cell adhesion, viability, proliferation, cytotoxicity according to ISO 10993-5, apoptosis and differentiation to adipocytes and osteoblasts on a variety of polymers (degradable biopolymers, degradable synthetic polymers, non-degradable synthetic polymers, shape memory polymers, and ceramics). RESULTS: Using this platform, biomaterials which support MSC growth by maintaining their stem cell characteristics and support the differentiation of MSC towards mature osteoblasts were identified. Furthermore, we showed that MSC possess fibrinolytic capacities and perform extracellular matrix remodelling. CONCLUSION: The data support the theory that MSC are involved in tissue regeneration both via their differentiation capacity and their trophic characteristics. We identified different MSC/biomaterial combinations which are suitable for stem cell-based bone tissue engineering.

[Mesenchymal stem cells for bone tissue engineering]. / Mesenchymale Stammzellen für das "tissue engineering" des Knochens.

Human mesenchymal stem cells (MSC) represent an attractive option for cell replacement strategies (tissue engineering, TE). TE applications require stability of a stem cell/biomaterial-hybrid via cell migration, matrix-remodelling and differentiation. We focus on these mechanisms in organotypic culture systems for bone TE using MSC from the umbilical cord (UC-MSC) and from bone marrow (BM-MSC). For the organotypic differentiation of MSC into functional osteoblasts, MSC were embedded in a collagenous matrix and subjected to osteogenic differentiation. Under these culture conditions, UC-MSC exceeded BM-MSC in the expression and synthesis of extracellular matrix (ECM) proteins, while BM-MSC show enhanced osteogenic gene upregulation. In both cell types the biosynthetic activity was accompanied by the ultrastructural appearance of hydroxyapatite/calcium crystals. Following secretion of matrix metalloproteinases, both MSC types migrated into and colonised the collagenous matrix causing matrix strengthening and contraction. In conclusion, MSC promise a broad therapeutical application for a variety of connective tissues requiring ECM synthesis and remodelling.

Torsade de pointes in a patient with complex medical and psychiatric conditions receiving low-dose quetiapine.

OBJECTIVE: Describe potential cardiac complications of low-dose quetiapine and other atypical antipsychotic drugs. METHOD: We present a case report of a 45-year-old Black woman with multiple medical and psychiatric problems taking low-dose quetiapine. RESULTS: Coincident with a generalized seizure, the patient developed 'ventricular fibrillation'. She was countershocked with restoration of normal sinus rhythm. The initial electrocardiogram showed QT interval prolongation. Shortly thereafter, classical torsade de pointes appeared, lasted 10 min, and resolved spontaneously. Hypomagnesemia was present. A cardiac electrophysiologist was concerned that the very slow shortening of the prolonged QTc interval after magnesium replacement implicated quetiapine as a risk factor for QTc interval prolongation and torsade de pointes. A psychosomatic medicine consultant asserted that the fragmented medical and psychiatric care almost certainly contributed to the patient's medical problems. We discuss other cases of QT interval prolongation by newer antipsychotic drugs and previous reports by our group concerning the association of psychotropic drugs, QT interval prolongation, and torsade de pointes. CONCLUSION: Atypical antipsychotic drug administration, when accompanied by risk factors, may contribute to cardiac arrhythmias including torsade de pointes.

Clinical features of treatment-resistant depression.

As many as 30% to 40% of patients with major depressive disorder are unresponsive to a trial of antidepressant medication. Many patients labeled with treatment-resistant depression actually have pseudoresistance, in that they have been inadequately treated or are misdiagnosed. Others may have unrecognized comorbid psychiatric or general medical conditions that contribute to treatment resistance. Variables such as gender, family history, age at onset, severity, and chronicity have also been evaluated as possible risk factors for treatment-resistant depression. This article reviews the current literature regarding the clinical characteristics of treatment-resistant depression, with particular attention to the relevance of these factors for clinical decision making.

Injury to the origin of the gastrocnemius muscle as a possible cause of lameness in four horses.

Four horses were evaluated because of hind limb lameness. Two had a distinct gait abnormality at the walk characterized by lateral rotation of the point of the calcaneus and medial rotation of the toe during the stance phase. Nuclear scintigraphy revealed a focal area of intense radioisotope uptake in the caudodistal aspect of the femur in all 4 horses, and 3 of the horses had a corresponding proliferative reaction on the caudodistal cortex of the femur on radiographs. In all 4 horses, a diagnosis of injury to the origin of the gastrocnemius muscle was made. Three of the horses returned to athletic endeavors after an extended period of rest and a gradual return to exercise. The fourth improved after 5 months of rest but became lame again when returned to exercise and was euthanatized.

Cardiopulmonary function in horses during anesthetic recovery in a hydropool.

OBJECTIVE: To determine the cardiovascular and respiratory effects of water immersion in horses recovering from general anesthesia. ANIMALS: 6 healthy adult horses. PROCEDURE: Horses were anesthetized 3 times with halothane and recovered from anesthesia while positioned in lateral or sternal recumbency in a padded recovery stall or while immersed in a hydropool. Cardiovascular and pulmonary functions were monitored before and during anesthesia and during recovery until horses were standing. Measurements and calculated variables included carotid and pulmonary arterial blood pressures (ABP and PAP respectively), cardiac output, heart and respiratory rates, arterial and mixed venous blood gases, minute ventilation, end expiratory transpulmonary pressure (P(endXes)), maximal change in transpulmonary pressure (deltaP(tp)max), total pulmonary resistance (RL), dynamic compliance (Cdyn), and work of breathing (W). RESULTS: Immersion in water during recovery from general anesthesia resulted in values of ABP, PAP P(endXes), deltaP(tp)max, R(L), and W that were significantly greater and values of Cdyn that were significantly less, compared with values obtained during recovery in a padded stall. Mode of recovery had no significant effect on any other measured or calculated variable. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in pulmonary and cardiovascular function between horses during recovery from anesthesia while immersed in water and in a padded recovery stall were attributed to the increased effort needed to overcome the extrathoracic hydrostatic effects of immersion. The combined effect of increased extrathoracic pressure and PAP may contribute to an increased incidence of pulmonary edema in horses during anesthetic recovery in a hydropool.

In vitro comparison of transfixation and standard full-limb casts for prevention of displacement of a mid-diaphyseal third metacarpal osteotomy site in horses.

OBJECTIVE: To compare transfixation and standard full-limb casts for prevention of in vitro displacement of a mid-diaphyseal third metacarpal osteotomy site in horses. SAMPLE POPULATION: 6 forelimbs from 6 horses euthanatized for reasons not related to the musculoskeletal system. PROCEDURE: A 30 degrees osteotomy was performed in the mid-diaphysis of the third metacarpal bone. Two 4.5-mm cortical bone screws were placed across the osteotomy site to maintain alignment during casting. Two 6.35-mm Steinmann pins were placed from a lateral-to-medial direction in the distal aspect of the radius. A full-limb cast that incorporated the pins was applied. An extensometer was positioned in the osteotomy site through a window placed in the dorsal aspect of the cast, and after removal of the screws, displacement was recorded while the limb was axially loaded to 5,340 N (1,200 lb). Pins were removed, and the standard full-limb cast was tested in a similar fashion. RESULTS: The transfixation cast significantly reduced displacement across the osteotomy site at 445 N (100 lb), 1,112 N (250 lb), 2,224 N (500 lb), and 4,448 N (1,000 lb), compared with the standard cast. CONCLUSION AND CLINICAL RELEVANCE: A full-limb transfixation cast provides significantly greater resistance than a standard full-limb cast against axial collapse of a mid-diaphyseal third metacarpal osteotomy site when the bone is placed under axial compression. Placement of full-limb transfixation casts should be considered for the management of unstable fractures of the third metacarpal bone in horses.

Long-term outcome of horses with a slab fracture of the central or third tarsal bone treated conservatively: 25 cases (1976-1993).

OBJECTIVE: To determine clinical features of horses with a slab fracture of the central or third tarsal bone and to report outcome of horses in which treatment did not include surgery. DESIGN: Retrospective study. ANIMALS: 25 horses (14 Standardbreds, 6 Thoroughbreds, 5 Quarter Horses). PROCEDURE: Medical records of horses with a slab fracture of the central (n = 9) or third (16) tarsal bone were reviewed. Only horses for which treatment consisted of confinement to a stall were included in this study. Clinical features and radiographic findings were recorded and summarized. Outcome was determined for racing breeds by obtaining official lifetime race results. Outcome for Quarter Horses was determined by phone survey of the owners. RESULTS: 16 (64%) horses had a successful outcome. Ten of 14 (71%) Standardbreds and 2 of 6 Thoroughbreds returned to racing and started at least 5 races after injury. Four of 5 Quarter Horses for which follow-up information was available successfully returned to their previous activity. Sex, age, limb affected, or gait was not associated with final outcome. Percentage of racehorses with central tarsal bone fractures that had a successful outcome (2/7) was significantly less than percentage with third tarsal bone fractures that did (10/13). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that enforced rest without surgical fixation can be an effective therapeutic option for horses with a slab fracture of the central or third tarsal bone, even if athletic function is expected.

Anesthesia of horses with a combination of detomidine, zolazepam, tiletamine, and isoflurane immediately after strenuous treadmill exercise.

OBJECTIVES: To evaluate effects of strenuous exercise in adult horses immediately before anesthesia and to determine whether prior exercise affects anesthesia induction, recovery, or both. ANIMALS: 6 healthy Thoroughbreds in good condition and trained to run on a treadmill, each horse serving as its own control. PROCEDURE: Horses ran on a treadmill until fatigued, then were sedated immediately with detomidine hydrochloride and anesthetized with a zolazepam hydrochloride-tiletamine combination. Anesthesia was maintained with isoflurane in oxygen for another 90 minutes. Blood samples were taken before, during, and after exercise and during anesthesia. RESULTS: During exercise, changes in heart rate, core body temperature, plasma lactate concentration, arterial pH, and PaCO2 were significant. Plasma ionized calcium concentration was lower after exercise, compared with baseline values, and remained lower at 30 minutes of isoflurane anesthesia. Compared with baseline values, plasma chloride concentration decreased significantly during anesthesia after exercise. Cardiac output during anesthesia was significantly lower than that during preexercise, but significant differences between experimental and control periods were not observed. Arterial blood pressure during anesthesia was significantly lower than that during preexercise and initially was maintained better during isoflurane anesthesia after exercise. Cardiac output and blood pressure values were clinically acceptable throughout anesthesia. CONCLUSION: Administration of detomidine hydrochloride followed by zolazepam hydrochloride-tiletamine appeared to be safe and effective for sedation and anesthesia of horses that had just completed strenuous exercise. CLINICAL RELEVANCE: Anesthetic given in accordance with this protocol can be used to anesthetize horses that are injured during athletic competition to assess injuries, facilitate first aid, and possibly allow salvage of injured horses.

Fractures of the rostral portion of the mandible and maxilla in horses: 89 cases (1979-1997).

OBJECTIVE: To compare fracture locations, repair methods, complications, and outcomes of horses with fractures of the rostral portions of the mandible and maxilla. DESIGN: Retrospective study. ANIMALS: 89 horses with fractures of the rostral portions of the mandible and maxilla. PROCEDURE: Medical records and radiographs were reviewed. Fractures were categorized by fracture location and stability. Postoperative complications and long-term outcome were determined by clinical examination and telephone interviews with horse owners. RESULTS: 4 fracture types were recognized. Fractures involving just the alveolar plate (33%) and those involving the alveolar plate and the body of the bone (32%) were most common and were often repaired by interdental wiring. Unilateral fractures of the mandible (11%) were managed without surgery if stable. Unstable fractures were repaired with wires, a U-shaped bar (U-bar), or a bone plate. Bilateral fractures (24%) were often repaired with orthopedic wires in foals or with a U-bar, acrylic splint, wires, or bone plate in adult horses. In 2 horses, bilateral fractures were managed conservatively. Short-term complications developed in 24 of 89 (27%) horses. Soft tissue infections and wire loosening or failure were the most common short-term and long-term complications. Wire replacement was not required in any horses after release from hospital. Persistent draining tracts were most often associated with bone sequestration. Long-term functional and cosmetic outcomes were favorable for all fracture types and repair methods. CLINICAL IMPLICATIONS: Although complications in horses with fractures of the mandible and maxilla are common, long-term prognoses for functional and cosmetic outcome are favorable.

Apical fracture of the proximal sesamoid bone in standardbred horses: 43 cases (1990-1996).

OBJECTIVE: To determine whether fracture fragment dimensions, suspensory ligament damage, and racing status at the time of injury were associated with outcome in Standardbred horses with apical fracture of the proximal sesamoid bone. DESIGN: Retrospective study. ANIMALS: 43 Standardbred racehorses. PROCEDURE: Medical records, racing records, and radiographs were reviewed, and ultrasonographic findings were scored. Measurements of the fractured portion of the proximal sesamoid bone were made. RESULTS: Seventy-four percent (32/43) of horses were pacers, and 26% (11/43) were trotters. Statistical differences between trotters and pacers regarding ability to start, number of starts, or amount of money earned after injury were not detected. Females earned significantly more money per start after injury than males. Eighty-six percent (37/43) of fractures involved hind limbs and 14% (6/43) involved forelimbs. Horses with forelimb injuries earned less money per start. Severity of suspensory ligament damage did not affect postinjury racing performance. A higher proportion of horses that had raced before injury returned to racing after surgery than horses that had not raced before injury, although a significant difference between these groups was not detected. Eighty-eight percent of horses that raced before injury raced after injury. Fifty-six percent of horses that did not race before injury raced after injury. Fracture fragment dimensions did not affect outcome. CLINICAL IMPLICATIONS: Dimensions of the apical fracture fragment of the proximal sesamoid bone in Standardbred horses and degree of suspensory ligament damage did not affect outcome. Prognosis for return to racing soundness is good in horses that had raced before injury and fair in horses that had not raced before injury.

Bone scintigraphy in the diagnosis of sacroiliac injury in twelve horses.

Nuclear bone scintigraphy was used to diagnose sacroiliac injury in 12 horses presented for nonspecific rear limb lameness. The most common history was decreased performance and/or a mild chronic rear limb lameness which could not be localised by routine lameness examination. The scintigraphic patterns of the 12 affected horses were compared to 5 normal horses and 10 horses with lameness not related to the pelvic region. Subjective and quantitative evaluation of the bone scans clearly separated the 12 affected horses from the 5 normal horses and the 10 horses with lameness from causes other than the sacroiliac joint disease. The 12 affected horses had a scintigraphic pattern of moderate to marked increased uptake of the radiopharmaceutical within the sacroiliac joint region on the side of lameness. In contrast, the 5 normal horses and 10 horses scanned for other causes of lameness, had a symmetric, or only slightly asymmetric pattern of radioisotope uptake. Although nonspecific for the type of injury, nuclear bone scintigraphy is considered sensitive for the detection of sacroiliac injuries in horses.

Effect of three types of half-limb casts on in vitro bone strain recorded from the third metacarpal bone and proximal phalanx in equine cadaver limbs.

OBJECTIVE: To determine effect of 3 half-limb casts on bone strains recorded from the proximal phalanx (P-1) and third metacarpal bone (MCIII) of equine cadaver limbs, using a mechanical testing machine. ANIMALS: 12 equine cadaver limbs and 4 live horses. PROCEDURE: Bone strains were recorded at middorsal P-1 and the dorsal cortical aspect of the distal third of MCIII while limbs were variably loaded with 100 to 1,000 lb of force. To determine ability of the cast to protect the distal portion of the limb from weight-bearing loads, strains were recorded with the limb in 1 of the 3 casts and with it unsupported. To determine cast-induced discomfort, weight-supporting and transfixation pin casts were evaluated on 2 live horses RESULTS: All 3 casts significantly reduced bone strain at P-1. Significant differences were observed: mean 61% reduction for the standard half-limb cast, 84% for the transfixation pin cast, and 97% for the weight-supporting cast at weight-bearing force of 500 lb. Only the weight-supporting cast significantly reduced strains recorded from MCIII. The weight-supporting cast was not well tolerated by 2 live horses. CONCLUSIONS: The 3 casts significantly reduced transfer of weight-bearing forces to the distal portion of the limb. The weight-supporting cast effectively reduced strain on the P-1 to near 0, but was well tolerated by live horses. The transfixation pin cast reduced strain on the P-1 by > 80% at weight-bearing loads of 500 lb, and live horses were comfortable. Standard half-limb casts significantly reduced strains on the P-1, but to a lesser degree than did other casts.

Effect of different full-limb casts on in vitro bone strain in the distal portion of the equine forelimb.

OBJECTIVE: To determine the ability of a full-limb transfixation pin cast to protect the distal portion of the equine forelimb from weight-bearing forces by measuring bone strain in vitro on cadaver limbs loaded in a mechanical testing machine. SAMPLE POPULATION: 6 forelimbs from 6 horses. PROCEDURE: Each limb was instrumented with 3 unidirectional metal foil electrical resistant strain gauges. Gauges were placed on the dorsal aspect of the distal portion of the radius and the mid-dorsal portion of the cortex of the third metacarpal bone and the first phalanx. Each limb was tested 3 times, once supported with a transfixation pin cast, once supported by a standard full-limb cast, and finally, uncast. The limbs were tested in a mechanical testing machine under axial loads ranging from 100 to 1,000 lb, and bone strains were recorded at each load. RESULTS: Compared with values for the uncast limb, the transfixation pin cast and the standard full-limb cast significantly (P < 0.001) reduced bone strain on the distal portion of the radius, third metacarpal bone, and first phalanx. Compared with the standard full-limb cast, the transfixation pin cast significantly (P < 0.001) reduced bone strain on the first phalanx. CONCLUSION AND CLINICAL RELEVANCE: Compared with the standard full limb cast, the full-limb transfixation pin cast is more protective of the first phalanx.

Effect of pin hole size and number on in vitro bone strength in the equine radius loaded in torsion.

OBJECTIVE: To determine the effect of pin hole size and number on the breaking strength of the adult equine radius when loaded in torsion to failure. SAMPLE POPULATION: 54 pairs of equine radii from adult horses. PROCEDURE: For test one, 12 pairs of radii were used to determine the effect of pin hole size on torsional breaking strength. A 6.35-mm hole was drilled in 1 radius, and a 9.5-mm hole was drilled in the contralateral radius. For test two, 36 pairs of radii were randomly assigned to 1 of 3 treatment groups (n = 12) to determine the effect of pin hole number on the torsional breaking strength of the equine radius. One radius of each pair served as a control, and one, three, or six 6.35-mm transcortical holes were drilled in the contralateral radius. For test three, 6 pairs of radii had torsional forces applied directly to the transfixation pins, as opposed to the bone itself. One radius of a pair served as a control, and three 6.35-mm smooth Steinman pins were placed in the contralateral radius. All radii were loaded in torsion to failure, and the breaking strengths were recorded. RESULTS: Compared with the 6.35-mm hole, the 9.5-mm hole significantly decreased torsional strength of the radius. There was no significant difference in mean torsional strength between the control radii and the radii with 1, 3, or 6 transcortical holes or when the transfixation pins were loaded. CONCLUSION: Use of up to three 6.35-mm transfixation pins can be used in a full-limb transfixation pin cast to optimize stiffness without a significant decrease (12%) in bone strength.