Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib.

Mutations of calreticulin (CALR) are detected in 25-30% of patients with essential thrombocythemia (ET) or primary myelofibrosis and cause frameshifts that result in proteins with a novel C-terminal. We demonstrate that CALR mutations activated signal transducer and activator of transcription 5 (STAT5) in 293T cells in the presence of thrombopoietin receptor (MPL). Human megakaryocytic CMK11-5 cells and erythroleukemic F-36P-MPL cells with knocked-in CALR mutations showed increased growth and acquisition of cytokine-independent growth, respectively, accompanied by STAT5 phosphorylation. Transgenic mice expressing a human CALR mutation with a 52 bp deletion (CALRdel52-transgenic mice (TG)) developed ET, with an increase in platelet count, but not hemoglobin level or white blood cell count, in association with an increase in bone marrow (BM) mature megakaryocytes. CALRdel52 BM cells did not drive away wild-type (WT) BM cells in in vivo competitive serial transplantation assays, suggesting that the self-renewal capacity of CALRdel52 hematopoietic stem cells (HSCs) was comparable to that of WT HSCs. Therapy with the Janus kinase (JAK) inhibitor ruxolitinib ameliorated the thrombocytosis in TG mice and attenuated the increase in number of BM megakaryocytes and HSCs. Taken together, our study provides a model showing that the C-terminal of mutant CALR activated JAK-STAT signaling specifically downstream of MPL and may have a central role in CALR-induced myeloproliferative neoplasms.

[Metastatic lung tumor from uterine leiomyosarcoma].

We herein present 2 cases of metastatic lung tumor derived from uterine leiomyosarcoma. In the case 1, a 59-year-old woman was admitted to our hospital to examine abnormal shadow detected on chest X-ray. She had undergone hysterectomy and oophorectomy for uterine leiomyosarcoma 19 months previously. A round 3 cm mass in the right lung (S10) was seen on chest X-ray and computed tomography (CT). No other distant metastases or local recurrence were found, and the right lower lobectomy was perfomed under the clinical diagnosis of metastatic lung tumor. Postoperative pathologic examination revealed the tumor as a metastatic leiomyosarcoma. The patient recovered uneventfully, and there have been no signs of recurrence for 26 months after the pulmonary resection. In the case 2, a 58-year-old woman, who had undergone hysterectomy and oophorectomy for uterine leiomyosarcoma 7 months previously, was admitted to our hospital for further examination of pulmonary tumors on chest X-ray. Two tumors were recognized in the left lung (S8 and S10) on chest X-ray and CT. No other distant metastases or local recurrence were found, and the left lower lobectomy was performed under the clinical diagnosis of metastatic lung tumors. Pathological examinations revealed smooth muscle cells with nuclear pleomorphism and high mitotic indices. The tumors proved to be lung metastases derived from uterine leiomyosarcoma. Postoperative course was uneventful. However, brain metastasis was found 1 month after the pulmonary resection, and she underwent resection of brain metastasis. Two months after the brain metastasectomy, local recurrence of the brain tumor developed and re-resection followed by stereotactic radiotherapy was performed. Furthermore, intrapelvic recurrence was found 4 months after the pulmonary resection. Exploratory laparotomy revealed the tumor was unresectable, and she received 4 courses of chemotherapy (paclitaxel and carboplatin). For metastatic lung tumor from uterine leiomyosarcoma, surgery has been considered the best choice. However, for patients with uterine leiomyosarcoma who cannot be treated surgically because of multiple metastatic tumors or poor surgical risk chemotherapy (paclitaxel and carboplatin) or stereotactic radiotherapy can be strategies.

[Small peripheral lung cancer incidentally detected by massive hemoptysis].

A 47-year-old man was admitted to our hospital for treatment of massive hemoptysis. He was intubated and underwent bronchial arterial embolization because of this deteriorating respiratory state and uncontrollable hemoptysis. Computed tomography (CT) of the chest showed a 1-cm nodular shadow in the peripheral apical lobe (S1) of the right lung. He underwent right upper lobectomy for the purpose of preventing re-hemorrhage as well as making the definitive diagnosis of nodular shadow in S1 of the right lung. Intraoperative pathological examination revealed the nodule as adenocarcinoma, and mediastinal lymphadenectomy was added to the right upper lobectomy. The patient recovered uneventfully, and there has been no sign of recurrence for 15 months after the operation.

The relative stress on the Achilles tendon during ambulation in an ankle immobiliser: implications for rehabilitation after Achilles tendon repair.

BACKGROUND: After Achilles tendon repair, immediate weightbearing and immobilisation closer to neutral plantarflexion are thought to limit atrophy and stiffness, but may place deleterious stress on the repair. OBJECTIVES: To estimate the relative stress on the Achilles tendon during weightbearing with immobilisation in varying degrees of plantarflexion. METHODS: Electromyographic (EMG) activity from the plantarflexors was recorded during walking in 10 subjects (six men, four women) without ankle pathology. Four walking conditions were examined: (a) normal walking; (b) immobilised (cam-walker) in neutral plantarflexion; (c) immobilised with a 0.5 inch heel lift; (d) immobilised with a 1 inch heel lift. EMG activity relative to plantarflexor torque was determined for each subject during isometric contractions at 25%, 50%, 75%, and 100% of maximal voluntary contraction (MVC). EMG activity during walking was calculated as a percentage of MVC based on the EMG-torque relation during graded isometric contractions. RESULTS: During normal walking, the plantarflexor torque was estimated to be 30 (12)% (mean (SD)) of MVC, compared with 21 (15)% MVC for immobilisation in neutral (p<0.05), 17 (15)% MVC with the addition of a 0.5 inch heel lift (p<0.01), and 12 (12)% MVC with the addition of a 1 inch heel lift (p<0.01). The 1 inch heel lift resulted in less than 10 degrees plantarflexion in all subjects. CONCLUSIONS: When the ankle is immobilised, stress on the Achilles tendon is determined by the degree of plantarflexion and the contractile activity of the plantarflexors. In the immobilised ankle, the addition of a 1 inch heel lift was sufficient to minimise plantarflexor activity during walking.

Quantitative assessment of walking activity after total hip or knee replacement.

Accumulating data suggest that the amount of use, and not simply the duration in situ, influences the wear and survival of total joint replacements. An electronic, digital pedometer was used to record the number of steps taken by 111 non-randomized volunteers who had had at least one total hip or knee replacement. The patients averaged 4988 steps per day, which extrapolates to approximately 0.9 million cycles per year for each joint of the lower extremity. Average activity ranged widely from 395 to 17,718 steps per day, an approximately forty-five-fold difference. The most active patient walked more than 3.5 times the average number of steps per day. Age was significantly associated with activity (p = 0.048), but there was a high degree of variability (standard deviation, 3040 steps per day). Patients who were less than sixty years old walked 30 per cent more on average than those who were sixty years old or more (p = 0.023). Men walked 28 per cent more on average than women (p = 0.037), and men who were less than sixty years old walked 40 per cent more on average than the rest of the patients (p = 0.011). These data indicate that individual differences in the activity of the patient can be a substantial source of variability in rates of polyethylene wear in vivo. The pedometer is an inexpensive investigational tool with many potential applications, including standardizing wear measurements of joint replacements on the basis of gait cycles rather than time. This quantitative approach may provide prognostic information regarding the survival of joint prostheses. Pedometer data may also be useful for quantitative assessment of walking ability in outcome studies.

Chest wall repair with a titanium instrument.

We performed chest wall repair with titanium alloy instruments as artificial ribs for prevention of paradoxical respiration and protection of the lung and liver after chest wall resection including the nearly entire length of the right seventh to the eleventh ribs and the costal arch for metastasis of osteosarcoma. The technique of this operation is presented diagrammatically.

Factors correlating with long term survival of McKee-Farrar total hip prostheses.

Clinical and radiographic evaluations of 15 McKee-Farrar hip replacements in 13 patients with followup of 21 to 26 years were performed. The average Harris hip score was 86 with no patients having a poor result. These patients outscored the age matched controls in all categories of the SF-36 health survey. All patients were community ambulators with qualitative activity levels exceeding the average for their age. Quantitative activity assessment with a pedometer in 3 patients indicated a current average of approximately 900,000 cycles per year. This represents more than 21 million cycles when extrapolated during the life of the implants. None of the femoral components were radiographically loose. One acetabular component may be loose. Osteolysis developed in 3 apparently well fixed femurs and in 1 acetabulum. There were several features of these cases that may have contributed to the long survival: (1) relatively small stature of the patients who averaged 160.5 cm (5 feet 5 inches) in height and 66.9 kg (147 lbs) in weight; (2) favorable biomechanics of the reconstruction with the hip center of rotation being medialized by an average of 6.4 mm and the femoral offset increased by an average of 4.9 mm; (3) decreased potential for neck socket impingement with an average lateral acetabular opening of 54 degrees and all components were anteverted; (4) radiolucent cement in 13 of 15 hips; and (5) no radiographically measurable wear. Previous analyses and comparisons of the clinical performance of the McKee-Farrar implant have focused on the metal on metal bearing. As has been recognized with the many variations of total hip replacement using metal on plastic hearings, there are a myriad of variables that contribute to clinical outcome. The results of this study suggest that patient selection and technical factors may contribute to the long term survival, and conversely to the failure, of McKee-Farrar implants.

The effect of ceruletide on tardive dyskinesia: a double-blind placebo-controlled study.

1. In a double-blind placebo-controlled study of 37 patients with tardive dyskinesia, the therapeutic effect of ceruletide was evaluated. 2. The patients were assigned at random to two groups that received either intramuscular injections of 0.8 micrograms/kg of ceruletide or placebo once weekly for 4 weeks. Conventional neuroleptic medication was not changed 3 weeks prior to and throughout the study period. Tardive dyskinesia was assessed using the Abnormal Involuntary Movement Scale over an 8-week period. 3. Ceruletide had a more pronounced effect on TD than the placebo however, because of the limited number of subjects examined, the difference between the two groups was not significant. Ceruletide was more effective than placebo in patients under 60 years of age (p less than 0.05) and whose antipsychotic medication was mainly butyrophenones. 4. No serious side effect was noted. 5. The findings suggested that ceruletide therapeutically benefits patients with tardive dyskinesia.

Similarities and differences between tau protein and chromobindin A.

Tau protein and Chromobindin A have several features in common but are not identical. Both consist of a small group of closely related proteins which can form aggregates. Both have a similar range of molecular weights (53-62 kDa) and isoelectric points (6.0-7.5). While Chromobindin A is known to be membrane associated, there is evidence that Tau protein also interacts with phospholipids. Both, not present in all tissues, can be found in the adrenal medulla. Despite these similarities both classes of proteins are unique and immunologically distinct. A rabbit antisera to Tau does not cross react with Chromobindin A. In addition, while protein kinase C and Ca/Calmodulin-dependent protein kinase II phosphorylate Tau protein, they do not phosphorylate Chromobindin A, demonstrating the specificity of these kinases for Tau protein phosphorylation.