Transplanted Murine Long-term Repopulating Hematopoietic Cells Can Differentiate to Osteoblasts in the Marrow Stem Cell Niche

Bone marrow transplantation (BMT) can give rise to donor-derived osteopoiesis in mice and humans; however, the source of this activity, whether a primitive osteoprogenitor or a transplantable marrow cell with dual hematopoietic and osteogenic potential, has eluded detection. To address this issue, we fractionated whole BM from mice according to cell surface immunophenotype and assayed the hematopoietic and osteopoietic potentials of the transplanted cells. Here, we show that a donor marrow cell capable of robust osteopoiesis possesses a surface phenotype of c-Kit⁺ Lin⁻ Sca-1⁺ CD34^−/lo, identical to that of the long-term repopulating hematopoietic stem cell (LTR-HSC). Secondary BMT studies demonstrated that a single marrow cell able to contribute to hematopoietic reconstitution in primary recipients also drives robust osteopoiesis and LT hematopoiesis in secondary recipients. These findings indicate that LTR-HSC can give rise to progeny that differentiate to osteoblasts after BMT, suggesting a mechanism for prompt restoration of the osteoblastic HSC niche following BM injury, such as that induced by clinical BMT preparative regimens. An understanding of the mechanisms that regulate this differentiation potential may lead to novel treatments for disorders of bone as well as methods for preserving the integrity of endosteal hematopoietic niches.     

Cerebral blood flow relationships associated with a difficult tone recognition task in trained normal volunteers

Tone recognition is partially subserved by neural activity in the right frontal and primary auditory cortices. First we determined the brain areas associated with tone perception and recognition. This study then examined how regional cerebral blood flow (rCBF) in these and other brain regions correlates with the behavioral characteristics of a difficult tone recognition task. rCBF changes were assessed using H2(15)O positron emission tomography. Subtraction procedures were used to localize significant change regions and correlational analyses were applied to determine how response times (RT) predicted rCBF patterns. Twelve trained normal volunteers were studied in three conditions: REST, sensory motor control (SMC) and decision (DEC). The SMC-REST contrast revealed bilateral activation of primary auditory cortices, cerebellum and bilateral inferior frontal gyri. DEC-SMC produced significant clusters in the right middle and inferior frontal gyri, insula and claustrum; the anterior cingulate gyrus and supplementary motor area; the left insula/claustrum; and the left cerebellum. Correlational analyses, RT versus rCBF from DEC scans, showed a positive correlation in right inferior and middle frontal cortex; rCBF in bilateral auditory cortices and cerebellum exhibited significant negative correlations with RT These changes suggest that neural activity in the right frontal, superior temporal and cerebellar regions shifts back and forth in magnitude depending on whether tone recognition RT is relatively fast or slow, during a difficult, accurate assessment.      

[3H]Neurotensin receptor densities in human postmortem brain tissue obtained from normal and schizophrenic persons. An autoradiographic study

Summary. [³H]Neurotensin binding and autoradiographic techniques were used to determine the distribution and density of neurotensin receptors in normal and schizophrenic postmortem brain tissue. Coronal hemi-brain blocks of tissue were cut at the level of the caudate and hippocampus from frozen brain tissue obtained from normal individuals with no known psychiatric or neurologic illnesses and from schizophrenic subjects off- or on-antipsychotic drugs at the time of death. Each hemi-block was further divided, sectioned, thaw mounted on to slides, incubated with [³H]neurotensin and apposed to film. Digitized images were analyzed for binding densities. Areas of intense binding include the substantia nigra, the entorhinal cortex, superficial layers of the cingulate, middle frontal, and insular cortices; and with moderate binding in nucleus accumbens, and caudate. Schizophrenic patients off- (3 months or more) or on-antipsychotic drugs at the time of death were tested; all patients showed a reduced level of neurotensin receptors in the caudate (68% of normals), cingulate (34%) and prefrontal cortices (25%). Accepted February 2, 1998; received October 8, 1997     

Opiate effects on plasma corticosteriods: relationship to dysphoria and self-administration

Narcotic analgesics have been shown to raise plasma corticosteroids in the rat. This effect has been interpreted as a response of the rat to the dysphoric properties of the drug. This interpretation is based on the observation that drugs such as nalorphine or cyclazocine which cause dysphoria in man elevate plasma corticosteroids in the rat at relatively low doses. Drugs like morphine or pentazocine which induce little dysphoria in man elevate plasma corticosteroids in the rat only at much larger doses. The corticosteroid-elevating effect is mediated by an opiate receptor since naloxone antagonizes the effect of morphine or the analgesic, U-50,488. Those narcotic analgesics which increased corticosteroid levels at low doses were also found to be poorly self-administered by rats. In contrast, compounds like morphine, pentazocine and the analgesic, U-49,274A, which were self-admistered at high rates, elevated corticosteroids only after large doses. The relationship between the dose of a drug which causes elevations in corticosteroid levels and whether or not the drug is self-administered further supports the premise that elevated corticosteroid levels induced by analgesics is due to their dysphoric properties.     

High incidence of low serum vitamin D concentration in patients with hip fracture

Summary The study of 82 consecutive hip fracture patients (22 males and 60 females) and 185 various controls showed that low serum 25-OH-vitamin D₃ (25-OD-D₃) concentration was common in the hip fracture patients, who in addition were old, incapable of independent daily life, had poor dietary habits, reduced nutritional status, and spent insufficient time in sunlight. The most usual mechanisms of trauma were minor indoor falls. Osteoporosis was common and associated with low 25-OH-D₃. Hypocalcemia was more common in hip fracture patients than in controls. Increased serum alkaline phosphatase was not a specific feature in hip fracture patients. The results suggest that vitamin D supplementation is indicated in elderly disabled people.

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Zusammenfassung Die Untersuchung einer geschlossenen Serie von 82 Patienten mit Huftfrakturen (22 männlich, 60 weiblich) und von 185 verschiedenen Kontrollfällen haben gezeigt, daß bei Patienten mit Hüftfrakturen häufig eine niedrige Serum-Konzentration von 25-OH-Vitamin D₃ (25-OH-D₃) bestand. Zusätzlich bestanden bei diesen Patienten ein hohes Lebensalter, Pflegebedürftigkeit, mangelhafte Ernährungsgewohnheiten, ein reduzierter Ernährungszustand und sie waren dem Sonnenlicht ungeniigend ausgesetzt. Den häufigsten Unfallmechanismus stellten leichtere Sturze in der Wohnung dar. Häufig bestand eine Osteoporose in Verbindung mit einem niedrigen 25-OH-D₃-Spiegel. Eine Hypokalzamie war bei den Patienten mit Hüftfrakturen häufiger als bei den Kontrollfällen, während die Konzentration der alkalischen Phosphatase nicht ein spezifisches Verhalten zeigte. Die Untersuchungsergebnisse legen bei älteren behinderten Menschen nahe, eine Vitamin D-Zufuhr durchzuführen.

     

Post-operative roentgenological findings and changes after mastoid obliteration

This study consisted of the evaluation of the plain X-ray findings of films taken at early follow-up (mean 1.5 months after surgery) and at late follow-up (4-14 years after the early films) of 211 ears which had been operated on radically and obliterated. Residual cells which were detected on the basis of the early films were associated with a more frequent occurrence of post-operative infection and were thus hallmarks of a poorer prognosis. Changes in the bone surrounding the surgical cavity and the radiological quality of the walls of the surgical cavity, the presence of new bone formation in the cavity and other radiological features did not yield useful information about post-operative complications. New bone formation was associated with a smaller amount of post-operative cavitation. Post-operative X-ray examination of the obliterated ear is a prognostically useful examination, but it does not significantly contribute further to the information available by clinical and otomicroscopic examination in regards to the complications of infection and cholesteatoma.     

JNK inhibitor SP600125 reduces COX-2 expression by attenuating mRNA in activated murine J774 macrophages

Inducible prostaglandin synthase (cyclooxygenase-2, COX-2) is highly expressed in inflammation. The signaling mechanisms involved in the up-regulation of COX-2 are not known in detail. In the present study we investigated the role of c-Jun NH2-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family in COX-2 expression and prostaglandin (PG) E2 production in murine J774 macrophages activated by bacterial lipopolysaccharide (LPS). LPS caused a transient activation of JNK which was followed by increased COX-2 expression. Anthra(1,9-cd)pyrazol-6(2H)-one (SP600125), an inhibitor of JNK, inhibited phosphorylation of c-Jun with an IC50 of 5-10 microM. At the same concentrations SP600125 suppressed also LPS-induced COX-2 protein levels and PGE2 production. SP600125 did not alter LPS-induced COX-2 mRNA levels when measured 3 h after addition of LPS, whereas mRNA levels were significantly reduced in SP600125-treated cells when measured 24 h after addition of LPS. LPS-induced COX-2 mRNA levels reduced faster in cells treated with SP600125 than in control cells. Cycloheximide (that is known to activate JNK) enhanced COX-2 expression and its effect was inhibited by SP600125. The present results suggest that JNK pathway is involved in the up-regulation of COX-2 expression possibly by a mechanism related to the stability of COX-2 mRNA.     

Expandable intramedullary nailing for tibial and femoral fractures: a preliminary analysis of perioperative complications

OBJECTIVE: To report the results of using the expandable nailing system in the treatment of femoral and tibial shaft fractures. DESIGN: Prospective, cohort series. SETTING: Two level-1 university trauma centers. PARTICIPANTS: Forty-eight patients with acute, traumatic diaphyseal fractures of the tibia or femur. INTERVENTION: Internal fixation of lower extremity long bone fractures using expandable intramedullary nailing. MAIN OUTCOME MEASUREMENTS: Perioperative complications and time to healing. RESULTS: Forty-nine long bone fractures were treated: 22 femoral fractures (OTA classification: 4 type A1, 6 A2, 7 A3, 1 B1, and 4 B2) and 27 tibial fractures (OTA classification: 4 type A1, 11 A2, 9 A3, 0 B1, and 3 B2). There were 13 open fractures and 37 closed fractures. Healing occurred in 37 (75%) fractures without additional interventions. There were 2 tibial delayed unions and 1 femoral and 1 tibial nonunion. Five tibial shaft fractures and 6 femoral fractures shortened by 1.0 cm or more postoperatively. In 3 tibias and 4 femurs, shortening occurred after fractures judged to be length-stable became unstable because of fracture propagation during nail expansion. Five tibias and 3 femurs were converted to standard locked nails because of shortening. The average time to healing, excluding nonunion, was 15 weeks in the tibia and 16 weeks in the femur. The expandable nail resulted in an unplanned reoperation in 12 cases (25%). CONCLUSION: We found a high complication rate because of shortening, which was independent of fracture classification. Consequently, we cannot recommend the use of an unlocked, expandable nail in diaphyseal fractures of the femur or tibia.