OVPSYCH2: A randomized controlled trial of psychological support versus standard of care following chemotherapy for ovarian cancer.

BACKGROUND: Fear of disease progression (FOP) is a rational concern for women with Ovarian Cancer (OC) and depression is also common. To date there have been no randomized trials assessing the impact of psychological intervention on depression and FOP in this patient group. PATIENTS AND METHODS: Patients with primary or recurrent OC who had recently completed chemotherapy were eligible if they scored between 5 and 19 on the PHQ-9 depression and were randomized 1:1 to Intervention (3 standardized CBT-based sessions in the 6-12 weeks post-chemotherapy) or Control (standard of care). PHQ-9, FOP-Q-SF, EORTC QLQ C30 and OV28 questionnaires were then completed every 3 months for up to 2 years. The primary endpoint was change in PHQ-9 at 3 months. Secondary endpoints were change in other scores at 3 months and all scores at later timepoints. RESULTS: 182 patients registered; 107 were randomized; 54 to Intervention and 53 to Control; mean age 59 years; 75 (70%) had completed chemotherapy for primary and 32 (30%) for relapsed OC and 67 patients completed both baseline and 3-month questionnaires. Improvement in PHQ-9 was observed for patients in both study arms at three months compared to baseline but there was no significant difference in change between Intervention and Control. A significant improvement on FOP-Q-SF scores was seen in the Intervention arm, whereas for those in the Control arm FOP-Q-SF scores deteriorated at 3 months (intervention effect = -4.4 (-7.57, -1.22), p-value = 0.008). CONCLUSIONS: CBT-based psychological support provided after chemotherapy did not significantly alter the spontaneously improving trajectory of depression scores at three months but caused a significant improvement in FOP. Our findings call for the routine implementation of FOP support for ovarian cancer patients.

Cardiac resynchronization therapy update: evolving indications, expanding benefit?

Cardiac resynchronisation therapy (CRT) is an effective intervention for appropriately selected patients with heart failure, but exactly how it works is uncertain. Recent data suggest that much, or perhaps most, of the benefits of CRT are not delivered by re-coordinating left ventricular dyssynchrony. Atrio-ventricular resynchronization, reduction in mitral regurgitation and prevention of bradycardia are other potential mechanisms of benefit that will vary from one patient to the next and over time. Because there is no single therapeutic target, it is unlikely that any single measure will accurately predict benefit. The only clinical characteristic that appears to be a useful predictor of the benefits of CRT is a QRS duration of >140 ms. Many new approaches are being developed to try to improve the effectiveness of and extend the indications for CRT. These include smart pacing algorithms, better pacing-site targeting, new sensors, multipoint pacing, remote device monitoring and leadless endocardial pacing. Whether CRT is effective in patients with atrial fibrillation or whether adding a defibrillator function to CRT improves prognosis awaits further evidence.

Dysregulated hematopoiesis and a progressive neurological disorder induced by expression of an activated form of the human common beta chain in transgenic mice.

Previously we described activating mutations of hbetac, the common signaling subunit of the receptors for the hematopoietic and inflammatory cytokines, GM-CSF, IL-3, and IL-5. The activated mutant, hbetacFIDelta, is able to confer growth factor-independent proliferation on the murine myeloid cell line FDC-P1, and on primary committed myeloid progenitors. We have used this activating mutation to study the effects of chronic cytokine receptor stimulation. Transgenic mice were produced carrying the hbetacFIDelta cDNA linked to the constitutive promoter derived from the phosphoglycerate kinase gene, PGK-1. Transgene expression was demonstrated in several tissues and functional activity of the mutant receptor was confirmed in hematopoietic tissues by the presence of granulocyte macrophage and macrophage colony-forming cells (CFU-GM and CFU-M) in the absence of added cytokines. All transgenic mice display a myeloproliferative disorder characterized by splenomegaly, erythrocytosis, and granulocytic and megakaryocytic hyperplasia. This disorder resembles the human disease polycythemia vera, suggesting that activating mutations in hbetac may play a role in the pathogenesis of this myeloproliferative disorder. In addition, these transgenic mice develop a sporadic, progressive neurological disease and display bilateral, symmetrical foci of necrosis in the white matter of brain stem associated with an accumulation of macrophages. Thus, chronic hbetac activation has the potential to contribute to pathological events in the central nervous system.

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFRC329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2V617F-positive clone in this PV patient harbors EGFRC329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2V617F disease clone in MPN.

Changes in arthroscopic findings in the anterior cruciate ligament deficient knee prior to reconstructive surgery.

We retrospectively compared the arthroscopic findings of 75 patients at the time of diagnosis of ACL rupture and the findings at the time of ACL reconstruction. We found that in the ACL deficient knee the deterioration in meniscal tears and osteochondral lesions was statistically greater with increased interval between diagnosis of ACL rupture and reconstruction. This study implies that in those patients where ACL reconstruction is indicated, a delay in reconstructive surgery can have a deleterious effect on the articular surface of the knee.

The effect of strict infection control policies on the rate of infection after elective foot and ankle surgery: a review of 1737 cases.

The rate of surgical site infection after elective foot and ankle surgery is higher than that after other elective orthopaedic procedures. Since December 2005, we have prospectively collected data on the rate of post-operative infection for 1737 patients who have undergone elective foot and ankle surgery. In March 2008, additional infection control policies, focused on surgical and environmental risk factors, were introduced in our department. We saw a 50% reduction in the rate of surgical site infection after the introduction of these measures. We are, however, aware that the observed decrease may not be entirely attributable to these measures alone given the number of factors that predispose to post-operative wound infection.

Calcium ionophore A23187 induces interleukin-8 gene expression and protein secretion in human monocytic cells.

The regulation of the expression of the interleukin-8 (IL-8) gene in human monocytic cell lines has been investigated. Agents such as interleukin-1 (IL-1) or interferon-gamma (IFN gamma) did not induce increased IL-8 expression in THP-1 or U937 cells. Bacterial lipopolysaccharide endotoxin (LPS) or phorbol myristate acetate (PMA) alone induced suboptimal expression as assessed by Northern blotting; however, preincubation of cells with PMA followed by endotoxin induced much higher levels of IL-8 mRNA. Incubation of the cells with the calcium ionophore A23187 resulted in consistent increased IL-8 gene expression comparable to that of cells treated with endotoxin alone. In addition to inducing IL-8 mRNA this calcium ionophore also induced IL-8 protein synthesis as assessed by immunofluorescence and secretion as detected by ELISA. These results indicate that increases in intracellular calcium result in IL-8 gene expression and protein secretion.

The resilience of combinatorial structure at the word level: morphology in self-styled gesture systems.

Combinatorial structure at both word and sentence levels is widely recognized as an important feature of language--one that sets it apart from other forms of communication. The purpose of these studies is to determine whether deaf children who were not exposed to an accessible model of a conventional language would nevertheless incorporate word-level combinatorial structure into their self styled communication systems. In previous work, we demonstrated that, despite their lack of conventional linguistic input, deaf children in these circumstances developed spontaneous gesture systems that were structured at the level of the sentence, with regularities identifiable across gestures in a sentence, akin to syntactic structure. The present study was undertaken to determine whether these gesture systems were structured at a second level, the level of the word or gesture--that is, were there regularities within a gesture, akin to morphological structure? Further, if intra-gesture regularities were found, how wide was the range of variability in their expression? Finally, from where did these intra-gesture regularities come? Specifically, were they derived from the gestures the hearing mothers produced in their attempt to interact with their deaf children? We found that all of the deaf children produced gestures that could be characterized by paradigms of handshape and motion combinations that formed a comprehensive matrix for virtually all of the spontaneous gestures for each child. Moreover, the morphological systems that the children developed, although similar in many respects, were sufficiently different to suggest that the children had introduced relatively arbitrary distinctions into their systems. These differences could not be traced to the spontaneous gestures their hearing mothers produced, but seemed to be shaped by the early gestures that the children themselves created. These findings suggest that combinatorial structure at more than one level is so fundamental to human language that it can be reinvented by children who do not have access to a culturally shared linguistic system. Apparently, combinatorial structure of this sort is not maintained as a universal property of language solely by historical tradition, but also by its centrality to the structure and function of language.

Molecular aspects of polycythemia vera (review).

Polycythemia vera (PV) is a rare, progressive myeloproliferative disorder thought to originate from the clonal expansion of a multipotent haemopoietic stem cell. This disease is characterised by hyperproliferation of the erythroid, myeloid and megakaryocyte lineages in the early phase, anaemia and fibrosis in the spent phase, and with a significant number of patients developing acute myeloid leukaemia (AML) in the final phase. Studies investigating the growth factor requirements of committed progenitors have shown hypersensitivity to a number of haemopoietic growth factors (HGF) in vitro and several HGF receptor and signalling molecule alterations have been reported. The findings to date, however, are unable to account for the transformation of a primitive stem cell and the many alterations to growth factor responses seen in PV progenitors. Identification of the primary lesion that leads to the pathogenesis of PV is of major importance given the profound effects on regulation of the haemopoietic stem cell compartment. In this article we focus on characteristics of the disease, research findings to date and possible mechanisms to explain altered growth factor responses, receptor alterations and signalling abnormalities in PV.

The influence on human osteoblasts in vitro of non-steroidal anti-inflammatory drugs which act on different cyclooxygenase enzymes.

There is increasing evidence that non-steroidal anti-inflammatory drugs (NSAIDs) can adversely affect bone repair. We have, therefore, studied the in vitro effects of NSAIDs, which differentially inhibit cyclooxygenases (COX), the prostaglandin/thromboxane synthesising enzymes, on human osteoblasts. Indomethacin and the new nitric oxide (NO)-donating NSAIDs block the activity of both COX-1 and COX-2. Indomethacin and 5,5-dimethyl-3-(3 fluorophenyl)-4-(4 methylsulphonal) phenyl-2 (5H)-furanone (DFU) reduced osteoblast numbers in a dose-dependant manner and increased collagen synthesis and alkaline phosphatase activity. The reduction in osteoblast numbers was not caused by loss of adhesion and was reversible. Neither NSAID influenced DNA synthesis. There was no difference between the effects of indomethacin and DFU. NO-NSAIDs did not affect cell numbers. These results suggest that care should be taken when administering NSAIDs to patients with existing skeletal problems and that NO-NSAIDs may be safer.

Mechanical partial small bowel obstruction in a patient with Fitz-Hugh-Curtis syndrome.

Perihepatitis or Fitz-Hugh-Curtis syndrome is a complication of pelvic inflammatory disease that usually leaves characteristic violin string adhesions on the anterior liver surface. These adhesions are common incidental findings on subsequent laparoscopy or laparotomy and are considered benign. We present a case of partial mechanical small bowel obstruction as a sequel of this syndrome that was diagnosed and treated laparoscopically.

A modified anaesthetic vapour extraction system.

A number of design modifications have been made to an extraction system for use with inhalation anaesthesia techniques in rats and other small laboratory animals. These changes necessitated a re-evaluation of the effectiveness of this equipment in limiting the operator's exposure to the anaesthetic vapours used. With a given fresh gas flow, the halothane vapour concentration in the operator's breathing zone was dependent on the design of the oronasal mask. With the optimum configuration the atmospheric concentration of halothane was less than 1 ppm.

Foreign body in the throat migrating through the common carotid artery.

We present a 55-year-old lady who swallowed a 3 cm pointed metal foreign body whilst eating a sardine salad. The foreign body migrated from the hypopharynx through the parapharyngeal space and traversed the common carotid artery over a period of 12 days. The foreign body was removed by exploration of the neck.

Growth factor plus preemptive ('just-in-time') plerixafor successfully mobilizes hematopoietic stem cells in multiple myeloma patients despite prior lenalidomide exposure.

Lenalidomide is associated with suboptimal autologous hematopoietic stem cell (AHSC) mobilization. We hypothesized that growth factor plus preemptive plerixafor is an effective strategy for AHSC mobilization in multiple myeloma (MM) despite prior exposure to lenalidomide. We retrospectively reviewed patient characteristics and mobilization outcomes of 89 consecutive MM patients undergoing first mobilization with filgrastim or pegfilgrastim +/- preemptive plerixafor using a previously validated algorithm based on day 4 peripheral blood CD34+ cell count (PB-CD34+) and mobilization target. Outcomes were analyzed according to the extent of prior exposure to lenalidomide: no prior exposure (group A, n=40), 1- 4 cycles (group B, n=30) and >4 cycles (group C, n=19). Multivariate analysis yielded only age and number of cycles of lenalidomide as negatively associated, and mobilization with pegfilgrastim as positively associated with higher PB-CD34+. Only 45% of patients in group A required plerixafor vs 63% in groups B and 84% in C, P=0.01. A higher proportion of patients in group A (100%) met the mobilization target than in groups B (90%) or C (79%), P=0.008. All patients yielded at least 2 × 10(6) CD34+/kg. Growth factor mobilization with preemptive plerixafor is an adequate upfront mobilization strategy for MM patients regardless of prior exposure to lenalidomide.

The prevalence of cognitive dysfunction after conventional and computer-assisted total knee replacement.

Post operative cognitive dysfunction (POCD) is common following lower limb arthroplasty. The prevalence varies from 41-75% at 7 days to 18-45% at 3 months post operatively. The wide range of prevalence is due to inconsistencies in defining and quantifying POCD. The aim of this study is to ascertain an accurate prevalence of POCD in patients who had either conventional TKR (n=31) or computer-assisted TKR (n=30). Cognition was assessed pre-operatively, 6 days and at 6 months post-operatively by a battery of 11 validated neuropsychological tests. We found the mean prevalence of POCD to be 72% at 6 days and 30% at 6 months post-operatively. When comparing the prevalence of POCD between the two groups, we found no statistically significant difference at 6 days or at 6 months post-operatively. The only statistically significant factor between the two groups was the mean procedure time which was longer in the computer-assisted TKR group (p=< 0.001). We found a correlation between procedure time and the prevalence of POCD at 6 days (p=0.02) but not 6 months (p=0.26). POCD occurs in approximately one-third of TKR patients at 6 months post-operatively. The cause is undoubtedly multi-factorial; however we have demonstrated that procedure time may be a contributing factor. Our results suggest that using an intra-medullary femoral jig has no effect on POCD. Further research into the cognitive effects following TKR with and without a tourniquet would be of benefit.