Plasma protein S deficiency in familial thrombotic disease

A family with a history of severe recurrent venous thromboembolic disease was studied to determine if a plasma protein deficiency could account for observed disease. Protein S levels in plasma were determined immunologically using the Laurell rocket technique. The propositus, his mother, his aunt, and his cousin who were clinically affected had 17% to 65% of the control levels of protein S antigen (normal range, 71% to 147%). Since three of these patients were receiving oral anticoagulant therapy, the ratios of protein S to prothrombin, factor X, and protein C in these patients were compared with values for a group of orally anticoagulated controls. These results suggested that protein S is half-normal in all family members with thrombotic disease. Other proteins known to be associated with familial thrombotic disease, including antithrombin III, plasminogen, fibrinogen, and protein C, were normal. Because plasma protein S serves as a cofactor for the anticoagulant activity of activated protein C and because protein C deficiency is associated with recurrent thrombotic disease, it is suggested that recurrent thrombotic disease in this family is the result of an inherited deficiency of protein S.     

Infrequent alterations of the RAR alpha gene in acute myelogenous leukemias, retinoic acid-resistant acute promyelocytic leukemias, myelodysplastic syndromes, and cell lines

Retinoids are important regulators of cell growth and differentiation in vitro and in vivo and they exert their biologic activities by binding to nuclear retinoic acid receptors (RARs; alpha, beta, and gamma) and retinoid X receptors (RXRs; alpha, beta, and gamma). All- trans retinoic acid (RA) induces complete remission in patients with acute promyelocytic leukemia (APL) presumably by binding directly to RAR alpha of APL cells. Leukemic blasts from APL patients initially responsive to RA can become resistant to the agent. HL-60 myeloblasts cultured with RA have developed mutations of the ligand-binding region of RAR alpha and have become resistant to RA. Furthermore, insertion of an RAR alpha with an alteration in the ligand-binding region into normal murine bone marrow cells can result in growth factor-dependent immortalization of the early hematopoietic cells. To determine if alterations of the ligand binding domain of RAR alpha might be involved in several malignant hematologic disorders, the mutational status of this region (exons 7, 8, and 9) was examined in 118 samples that included a variety of cell lines and fresh cells from patients with myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), including 20 APL patients, 5 of whom were resistant to RA and 1 who was refractory to RA at diagnosis, using polymerase chain reaction-single- strand conformational polymorphism (PCR-SSCP) analysis and DNA sequencing. In addition, 7 of the 20 APLs were studied for alterations of the other coding exons of the gene (exons 2 through 6). No mutations of RAR alpha were detected. Although the sensitivity of PCR-SSCP analysis is less than 100%, these findings suggest that alterations of RAR alpha gene are rare and therefore other mechanisms must be involved in the onset of resistance to retinoids and in the lack of differentiation in disorders of the myeloid lineage.     

Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) in primary effusion lymphoma: ultrastructural demonstration of herpesvirus in lymphoma cells

Recent molecular evidence suggests an association with a new herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8), and primary effusion lymphomas (PELs). PELs have a characteristic morphology, phenotype, and clinical presentation, with malignant effusions in the absence of a contiguous solid tumor mass. We have established a cell line (KS-1) from a KSHV-positive human immunodeficiency virus (HIV)-negative patient with pleural cavity-based lymphoma that was passaged into triple-immunodeficient BNX mice. In contrast to cell lines from body cavity-based lymphomas derived from HIV-positive individuals that contain both KSHV and Epstein Barr viral genome, these cells contain only KSHV, allowing for uncontaminated virologic studies. Ultrastructural examination identified malignant cells with features of late differentiating B cells (immunoblasts). Cells with viral cytopathic effect contained typical 110-nm intranuclear herpesvirus nucleocapsids and complete cytoplasmic virions, confirming the association of PEL with KSHV.     

Synergistic effects of thrombopoietin and granulocyte colony- stimulating factor on neutrophil recovery in myelosuppressed mice

Severe suppression of the hematopoietic system is a major factor in limiting chemotherapy dose escalation. To determine whether a combination of human recombinant granulocyte colony-stimulating factor (G-CSF) and thrombopoietin (TPO) would alter recovery of platelets, red blood cells (RBCs), or neutrophils after myeloablative therapy, myelosuppressed mice were treated with sc injections of TPO (90 micrograms/kg), G-CSF (250 micrograms/kg). TPO plus G-CSF or vehicle and complete blood counts were measured. Marrow and spleen cells were obtained at various times and assayed for erythroid, myeloid, and megakaryocytic progenitors. The prolonged neutropenia in vehicle controls (14 days) was significantly shortened in mice treated with G- CSF or TPO for 14 days. The combination of TPO plus G-CSF further reduced the duration of neutropenia. TPO and TPO plus G-CSF treatments also significantly shortened thrombocytopenia compared to vehicle. Recovery of RBCs was also enhanced in mice treated with either G-CSF or TPO, or the combination. Furthermore, treatment with G-CSF and/or TPO hastened myeloid, erythroid, and megakaryocyte progenitor recovery compared to vehicle controls. These results show that the combination of TPO plus G-CSF acts synergistically to accelerate neutrophil recovery in myelosuppressed mice and does not compromise the platelet or RBC response to TPO therapy.     

Detection of ubiquityl-calmodulin conjugates with a novel high-molecular weight ubiquitylprotein-isopeptidase in rabbit tissues

The selective degradation of many proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved protein [1]. Ubiquitylated proteins were degraded by the 26S proteasome in an ATP-depended manner. The degradation of ubiquitylated proteins were controlled by isopeptidase cleavage. A well characterised system of ubiquitylation and deubiquitylation is the calmodulin system in vitro [2]. Detection of ubiquityl-calmodulin conjugtates in vivo have not been shown so far. In this article we discuss the detection of ubiquitin calmodulin conjugates in vivo by incubation with a novel high-molecular weight ubiquitylprotein-isopeptidase in rabbit tissues. Proteins with a molecular weight of ubiquityl-calmodulin conjugates could be detected in all organs tested. Incubation with ubiquitylprotein-isopeptidase showed clearly a decrease of ubiquitin calmodulin conjugates in vivo with an origination of unbounded ubiquitin. These results suggest that only few ubiquitin calmodulin conjugates exist in rabbit tissues.     

Do clinical characteristics and outcome in nonagenarians with a hip fracture differ from younger patients?

Aim: To compare clinical characteristics and outcome of nonagenarian hip fracture patients with younger patients aged 65–89 years. Methods: This was a cohort follow‐up study of admissions for a hip fracture between 2005–2010 (mean follow up of 3.5 years) in two teaching hospitals in the Netherlands; 230 nonagenarians and 1014 patients aged 65–89 years were included. Clinical characteristics, adverse events, mobility and mortality were compared. Results: Nonagenarians were more likely to be female and anemic (both P < 0.001), and had more trochanteric fractures (P = 0.005). The number of American Society of Anesthesiologists III/VI classified patients did not differ between the two groups. During the hospital stay, adverse events were more frequently observed in nonagenarians compared with younger patients (P < 0.001). The length of stay was significantly longer in nonagenarians (P < 0.001), and the 90‐day readmission rate was similar. Absolute mortality was higher in nonagenarians (P < 0.001), excess mortality, however, was comparable. Before admission, 40.0% of the nonagenarians lived in their own home, and 40.9% had returned 3 months postfracture. The rate of returning to their own home was lower compared with younger patients (P < 0.001). Prefracture mobility was worse in nonagenarians compared with the younger group, but 3 months after discharge, the number of patients that regained prefracture mobility was comparable in both age groups. Conclusions: Nonagenarian hip fracture patients differ significantly from younger patients aged 65–89 years with respect to clinical characteristics and long‐term outcome. However, almost half of the nonagenarians returned to their own home and more than half regained their prefracture level of mobility. Given these findings, prevention strategies for hip fracture and adverse events during hospital stay that focus particularly on frail nonagenarians are highly recommended. Geriatr Gerontol Int 2013; 13: 190–197.     

High-intensity focused ultrasound (HIFU) followed after one to two weeks by radical retropubic prostatectomy: results of a prospective study

BACKGROUND: High-intensity focused ultrasound (HIFU) consists of focused ultrasound waves emitted from a transducer that are capable of inducing tissue damage. Experimental studies have shown clear damage of malignant tissue exposed to HIFU, but knowledge of in vivo effects is limited. We studied the safety and efficacy of HIFU in patients with a T1-2 N0) M0 prostate carcinoma. METHODS: HIFU treatment was performed under general anesthesia with the Ablatherm device (Technomed Medical Systems, Lyon, France), 7-12 days prior to radical prostatectomy. Only the lobe in which carcinoma was confirmed was treated. The radical prostatectomy specimen was examined histopathologically, and the changes were compared with treatment goals. RESULTS: So far, 9 patients have been treated. On histology, a sharp delineation was noted between areas treated with HIFU and untreated areas. On the dorsal border, however, incomplete destruction of tissue was noted, and in 2 cases a small residual tumor was seen in this region. In all cases complete necrosis was seen in the treated region. CONCLUSIONS: Histology reports of radical prostatectomy specimens of patients operated 7-12 days after HIFU treatment showed marked and complete necrosis in the treated area. Due to incomplete tissue destruction at the dorsal side, however, a small focus of residual vital tumor was found in 2 of 9 patients.     

异丙酚复合氯胺酮全麻诱导对血流动力学的影响

0　引言　我们观察氯胺酮对异丙酚静脉复合诱导时血流动力学的影响 ,并以芬太尼复合异丙酚全麻诱导做对照研究 .1　对象和方法1.1　对象　 30例 ASA ～ 级择期行全麻手术的患者 .男2 0例 ,女 10例 ,年龄 18～ 5 5岁 ,体质量 49～ 75 kg,随机分为两组 ,A组为异丙酚复合氯胺酮组 ,B组为异丙酚复合芬太尼组 ,每组 15例 .1.2　方法　术前 30 min im苯巴比妥钠 0 .1g,阿托品 0 .5mg. A组诱导为 iv异丙酚 2 mg· kg- 1 ,氯胺酮 1mg· kg- 1及维库溴胺 0 .1mg· kg- 1 . B组为 iv异丙酚 2 m g· kg- 1 ,芬太尼 2 μg· kg- 1 及维库溴胺 0 .1mg…     

Close mapping of the focal non-epidermolytic palmoplantar keratoderma (PPK) locus associated with oesophageal cancer (TOC)

Focal non-epidermolytic palmoplantar keratoderma (PPK or palmoplantar ectodermal dysplasia type III) is associated with oesophageal cancer in three families: two large pedigrees located in Liverpool, UK and in the midwestern American states and one smaller family from Germany. In these families, the PPK is inherited as autosomal dominant and has a late onset, usually manifesting between 7 and 8 years of age. The disease is characterised by thickening of the pressure areas of the soles, but is not restricted to the feet and also presents with oral leukokeratosis and follicular hyperkeratosis. The disease locus [previously termed the "tylosis oesophageal cancer gene' (TOC) locus] has been mapped to 17q23-qter by linkage analysis. This region is located telomeric to the keratin 16 gene, in which mutations have been identified in focal PPK families who show no increased cancer risk. We describe the close mapping of this locus to the interval between AFMb054zf9 and D17S1603 using haplotype analysis of additional Genethon markers in the region and show that although the American family is unlikely to be related to either of the other two, the UK and German pedigrees may share a common descent. This work provides a basis for positional cloning and candidate gene analysis in order to identify a gene that may be involved in familial oesophageal cancer.