The effect of etidronate on the periodontium of ovariectomized rats

Background: Bisphosphonates are indicated for the treatment of osteoporosis. However, they could have an adverse effect on specific sites, such as the bisphosphonate‐related osteonecrosis of the jaw. The aim of this study is to investigate the effect of etidronate on the resorption and apposition sides of the periodontium in ovariectomized rats. Methods: Twenty‐four female Wistar rats were randomly subjected to either ovariectomy or sham operation. After 8 weeks, six animals of each group were sacrificed. The other 12 rats received 5 mg/kg/day etidronate subcutaneously during 4 weeks. Tartrate‐resistant acid phosphatase reaction and immunohistochemical staining for receptor activator of nuclear factor‐κB (RANK), RANK‐ligand (RANKL), osteoprotegerin (OPG), and osteocalcin was performed. Immunoreactivity was evaluated using a semiquantitative analysis. Results: In ovariectomized rats, osteoclasts were noticed in the root socket of molars, including the apposition side of the periodontium, in which RANKL expression was significantly evidenced. In the etidronate‐treated group, OPG expression was significantly expressed and osteoclasts that were noticed in the resorption side remained undetected in the apposition side even under ovariectomy. RANK was significantly expressed in ovariectomized rats treated with etidronate. Osteoid formation and osteocalcin expression were described on the alveolar bone surfaces in etidronate‐treated rats, with or without ovariectomy. Conclusions: Etidronate has specific site and bone cell actions in the periodontium. It inhibits the osteoclast differentiation induced by ovariectomy in the apposition side of the periodontium but maintains bone formation over all the socket surfaces. Such specificity may be related to the pathogenesis of the bisphosphonate‐induced osteonecrosis of the jaw.     

CD48 May serve as an accessory molecule for the activation of a subset of human γ/δ T cells

To further assess the role of CD48 in the interaction of human γ/δ T cells with their specific target, we generated two series of alloreactive clones, L and K. These clones express a V1-D-J1-C δ chain associated to V3-J2-C2 (L) or V2-J2-C2 (K) γ chain. Functionally they were CTLs able to lyse the sensitizing B-cell line E418. The cytotoxicity of the L and K clones toward E418 was inhibited by anti-CD48 mAb. That of the L clones was also inhibited by anti-HLA class I mAbs. Variation in L and K lysis profile was observed against a panel of CD48 targets, further strengthening the argument that they display distinct specificities and suggesting that they do not recognize CD48. Heterogeneity in TCR gene segment usage, MHC-dependent recognition of E418 by the L clones, and resistance of some CD48⁴ targets strongly suggest that CD48 itself does not interact with L and K TCR. Transfection of CHO cells with CD48 induced killing by the K clones. This killing was inhibited by anti-CD48 mAbs. Taking into account the recent reports on CD48 as an accessory molecule, our results suggest that by binding to CD2 (and/or an unknown ligand), CD48 may serve to strengthen E/T interaction and may contribute to the activation of a minor subset of γ/δ T cells.     

Outcome of older patients with acute myeloid leukemia in first relapse

To provide data for future drug evaluation, we analyzed the outcome of 393 patients aged 50 years or older (median, 64 years) with AML in first relapse after treatment in recent ALFA trials. Salvage options were retrospectively classified as follows: best supportive care (BSC), low‐dose cytarabine (LDAC), gemtuzumab ozogamicin (GO), intensive chemotherapy (ICT), or ICT combined with GO. Second complete remission (CR2) rate was 31% and median post‐relapse survival was 6.8 months (0, 17, 42.5, 53, and 80% and 3.2, 5.6, 8.9, 9, and 19.8 months in BSC, LDAC, GO, ICT, and ICT + GO subsets, respectively). Age, performance status, WBC, CR1 duration, and favorable AML karyotype, but not other cytogenetic or molecular features, influenced post‐relapse outcome. Multivariate adjustment and propensity score matching showed that intensive salvage (ICT/ICT+GO/GO versus LDAC/BSC) was associated with longer post‐relapse survival, at least in patients with CR1 duration ≥12 months (P = 0.001 and 0.0005, respectively). Of interest, GO appeared to be as effective as standard ICT, and ICT + GO combination more effective than standard ICT. In conclusion, older patients with CR1 duration ≥12 months appeared to benefit from intensive salvage and results observed with GO‐containing salvage suggest that GO combination studies should be actively pursued in this setting. Am. J. Hematol. 88:758–764, 2013. © 2013 Wiley Periodicals, Inc.     

Deficiency in calcineurin activity in liver transplantation candidates with alcoholic cirrhosis or hepatocellular carcinoma

Background: Tacrolimus and cyclosporin inhibits the activity of calcineurin, a serine/threonine phosphatase that is involved in many physiological and pathological pathways. However, the baseline calcineurin phosphatase activity (CPA) measured before the transplant is unknown. In this study, we determine baseline CPA in liver transplant (LT) candidates and explore some factors that might modify it. Patients and methods: Thirty‐two consecutive LT candidates (25 men, seven women, average age 53.4 years) were included. Seven millilitres of whole blood was collected from each patient. CPA was determined in lymphocytes quantifying a dephosphorylated peptide phosphorylated previously (D‐L‐D‐V‐P‐I‐P‐G‐R‐F‐D‐R‐R‐V‐S‐V‐A‐A‐E) by high‐performance liquid chromatography. The relationship between CPA and the quantitative variables was tested according to Pearson's correlation. A two‐way analysis of variance was performed to test the independent role of categorical parameters in CPA. Results: The median CPA was significantly lower in LT candidates than in healthy volunteers [179.2 (146.9–226.3) vs 247.8 (220.9–292.5) pmol/min/10⁶ peripheral blood mononuclear cell (PBMC), respectively, P=0.0002]. CPA was also significantly lower in alcoholic cirrhosis (152.2 vs 211.1 pmol/min/10⁶ PBMC, P=0.04) and in the presence of hepatocellular carcinoma (HCC) (152.0 vs 213.5 pmol/min/10⁶ PBMC, P=0.0074) compared with other liver diseases. A two‐way analysis of variance showed that these parameters were independently associated with lower CPA (P=0.05 for alcohol and P=0.0056 for HCC respectively). Conclusion: This pilot study showed a lower CPA in patients with AC and HCC. This phenomenon may contribute towards lowering the risk of acute rejection in these patients after LT and, on the other hand, may increase the risk of de novo cancers.     

An evaluation of antibody detection of the P2X1 receptor subunit in the CNS of wild type and P2X1-knockout mice

P2X receptors in the nervous system are involved in both neuronal and glial functions. Pharmacological tools to differentiate the seven P2X subunits are limited, hence localisation studies have examined their distribution. Such studies have provided conflicting data on the localisation of the P2X1 receptor subunit in the CNS. We therefore tested for the presence of the P2X1 subunit in the CNS, using tissue from P2X1 subunit knockout (KO) mice to test the antisera. There was no difference between the CNS of wild type (WT) and KO mice using anti-P2X1 in immunohistochemistry and Western blots. In contrast, the bladder reacted positively only in WT tissue. Thus the P2X1 subunit antibodies cross-react with non-P2X1 receptor proteins in the CNS. Antibody specificity tests should therefore be conducted in the specific tissue to be examined and on KO tissue where available.     

The arterial supply of the temporalis muscle

Owing to the diverse applications of the temporalis muscle in reconstructive surgery, the study of its arterial supply is becoming an issue of great importance nowadays. The material of the present study consisted of 44 specimens, four obtained from two stillbirths and 40 dissected from 20 embalmed cadavers after injecting the external carotid artery with lead oxide solution. Direct branches from the second part of the maxillary artery and the middle temporal artery proved to be constantly furnishing the muscle from its superficial and deep surfaces. The muscular branch of the middle temporal artery supplied the middle and posterior thirds of the superficial surface and the posterior third of the medial surface of the muscle. The superficial temporal artery participated in supplying the muscle from its lateral surface, while the anterior and posterior deep temporal arteries lay deep to the anterior and the middle thirds of the muscle, respectively. The temporal branches of the middle meningeal artery anastomosed with the deep temporal arteries, thereby contributing to the supply of the temporalis muscle. An arterial pedicle arising from the third part of the maxillary artery constituted an additional supply in 9.1% of the specimens, providing an additional arterial pedicle for temporalis-muscle-flap elevation.     

Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma

BACKGROUND: Malignant pancreatic endocrine tumors (PETs) have a poor prognosis and existing antitumor treatments are unsatisfactory. Recent studies have shown somatostatin analogues to have antitumor growth effects in patients with malignant PETs; however, to the authors' knowledge, little information exists regarding their efficacy or effect on survival in patients with progressive malignant gastrinoma, the most common symptomatic malignant PET. The purpose of the current study was to study prospectively the efficacy, safety, and effect on survival of long-term treatment with octreotide in consecutive patients with progressive malignant gastrinoma. METHODS: Fifteen consecutive patients with malignant gastrinoma with progressive hepatic metastases were studied. All patients underwent conventional imaging studies (computed tomography scan, magnetic resonance imaging, ultrasound, and, if needed, selective angiography) and somatostatin receptor scintigraphy prior to treatment and at 3-6-month intervals while receiving treatment. The patients all were treated initially with octreotide, 200 microg every 12 hours, and at last follow-up were being maintained on long-acting release octreotide, 20-30 mg every month. Tumor size and/or number were used to classify patient responses as either no tumor response or tumor response (stabilization or decrease in size). Treatment response was correlated with tumor and clinical characteristics. RESULTS: Tumors in 8 of the 15 patients studied (53%) responded at 3 months, with 47% (7 of 15 patients) demonstrating tumor stabilization and 6% (1 of 15 patients) demonstrating a decrease in tumor size. The mean duration of response was 25.0+/-6.1 months (range, 5.5-54.1 months). Six of the eight responders were continuing to respond at the time of last follow-up. Tumor response did not correlate with any clinical parameter (e.g., tumor extent, fasting gastrin, or acid secretory rates). However, slow-growing tumors were more likely to respond prior to treatment (86% vs. 0%) (P < 0.0014). During follow-up (range, 4-8 years), 25% of the responders died compared with 71% of the nonresponders, a difference that approached statistical significance (P = 0.10). Two patients (13%) developed serious side effects that required the withdrawal of octreotide. CONCLUSIONS: Octreotide is an effective antitumor treatment in patients with progressive malignant gastrinoma. In approximately 50% of these patients octreotide has an antigrowth effect; treatment is associated with a low incidence of serious side effects compared with other antitumor treatments commonly used and, in contrast to many studies, the growth response is long-lasting. The results of the current study suggest that octreotide treatment should replace chemotherapy as the standard treatment for these patients, especially those patients with slow-growing tumors. Additional studies involving larger numbers of patients will be needed to determine a convincing effect on survival.     

Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1

BACKGROUND: Hyperparathyroidism in patients with multiple endocrine neoplasia type 1 (MEN1) is characterized by multiglandular disease and a propensity for recurrence after parathyroidectomy (PTx). This study analyzes outcomes of a cohort of MEN1 patients undergoing initial PTx at one institution. METHODS: Between April 1960 and September 2002, 92 patients with MEN1 underwent initial PTx. Outcomes were analyzed based on extent of parathyroid resection. RESULTS: Fourteen percent had 2.5 or fewer glands resected, 69% had subtotal PTx, and 17% had total PTx (88% with immediate autotransplantation). The initial surgical cure rate was 98%. Excluding 6 patients lost to follow-up, 33% have developed recurrent hyperparathyroidism (in 46% after < or =2.5 PTx, in 33% after subtotal, and in 23% after total PTx). Median recurrence-free survival was not statistically significantly different between subtotal versus total PTx, but it was longer for subtotal and total PTx compared with lesser resection (16.5 vs 7.0 years, respectively, P=.03). The incidence of severe hypoparathyroidism was 46% after total versus 26% after subtotal PTx. CONCLUSIONS: Subtotal and total PTx result in durable control of MEN1-associated hyperparathyroidism and have longer recurrence-free intervals compared with lesser resection. The high incidence of severe hypoparathyroidism after total PTx suggests that subtotal PTx is the initial operation of choice in this setting.