Resorptive hypercalcemia in post-essential thrombocythemia myelofibrosis: treatment with denosumab

Context: Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known. Objective: We report a unique case of hypercalcemia associated with post-essential thrombocythemia myelofibrosis and review the clinical and laboratory features, pathogenesis, and responsiveness to treatment with the bone antiresorptive agent, denosumab. Results: A 62-yr-old woman with essential thrombocythemia presented with progression to myelofibrosis with lytic skull lesions and symptomatic hypercalcemia. Other causes of hypercalcemia were excluded. Her disturbance in calcium homeostasis was not PTH- or vitamin D-mediated, although this has been postulated in cases of hypercalcemia with the related entity of primary myelofibrosis. Her hypercalcemia was refractory to aggressive iv saline administration, furosemide, calcitonin, and pamidronate, but promptly improved after one 120-mg sc dose of the anti-receptor activator of nuclear factor κB (RANK) ligand monoclonal antibody, denosumab, with sustained normocalcemia for approximately 2 months. She died 6 months later from complications due to the leukemic transformation of her hematological disease. Conclusion: The pathogenesis of myelofibrosis-related hypercalcemia could be due to multiple factors, particularly changes in the RANK ligand-RANK-osteoprotegerin system that lead to increased osteoclast activity. Although we did not measure these factors, denosumab holds promise in the treatment of malignancy-associated hypercalcemia and specifically that related to myelofibrosis. Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known.     

Synaptic plasticity and the analysis of the field-EPSP as well as the population spike using separate recording electrodes in the dentate gyrus in freely moving rats

Commonly, synaptic plasticity events such as long-term potentiation (LTP) are investigated by using a stimulation electrode and a single, monopolar field recording electrode in the dentate gyrus in intact, freely moving rats. The recording electrode is mostly positioned in the granular cell layer, or the hilar region of the dentate gyrus, i.e. far away from the place of generation of monosynaptic postsynaptic excitatory potentials (EPSP). Since LTP is a synaptic phenomenon and field recordings far away from the activated synapses do not guarantee a specific interpretation of the overlaid, mixture of complex potentials of several different electrical fields it is often difficult or even impossible to interpret the data obtained by such a single recording electrode. Therefore, at least a separate or two recording electrodes should be used to record the EPSP as well as the spike, respectively, ideally at their places of generation. Here, we describe a method by implanting a chronic bipolar recording electrode which fulfils the above requirements by recording the field-EPSP as well as the population spike at their places of generation and describe the time course of LTP measured using this “double-recording” electrode. We show that different tetanization protocols resulted in EPSP- or population spike-LTP but only if the potentials were recorded by electrodes positioned within adequate places of potential generation. Interestingly, the commonly used recording in the hilus of a distinct part of a potential, mistakenly analyzed as an “EPSP” did not reveal any LTP.     

A Conceptual Definition of Vocational Rehabilitation Based on the ICF: Building a Shared Global Model

Background The International Classification of Functioning, Disability and Health (ICF) is a conceptual framework and classification system by the World Health Organization (WHO) to understand functioning. The objective of this discussion paper is to offer a conceptual definition for vocational rehabilitation (VR) based on the ICF. Method We presented the ICF as a model for application in VR and the rationale for the integration of the ICF. We also briefly reviewed other work disability models. Results Five essential elements of foci were found towards a conceptual definition of VR: an engagement or re-engagement to work, along a work continuum, involved health conditions or events leading to work disability, patient-centered and evidence-based, and is multi-professional or multidisciplinary. Conclusions VR refers to a multi-professional approach that is provided to individuals of working age with health-related impairments, limitations, or restrictions with work functioning and whose primary aim is to optimize work participation. We propose that the ICF and VR interface be explored further using empirical and qualitative works and encouraging stakeholders?? participation.     

HPV testing as a triage for borderline or mild dyskaryosis on cervical cytology: results from the Sentinel Sites study

Background:

Earlier pilot studies of human papillomavirus (HPV) triage concluded that HPV triage was feasible and cost-effective. The aim of the present study was to study the impact of wider rollout of HPV triage for women with low-grade cytology on colposcopy referral and outcomes.

Methods:

Human papillomavirus testing of liquid-based cytology (LBC) samples showing low-grade abnormalities was used to select women for colposcopy referral at six sites in England. Samples from 10 051 women aged 25–64 years with routine call or recall cytology reported as borderline or mild dyskaryosis were included.

Results:

Human papillomavirus-positive rates were 53.7% in women with borderline cytology and 83.9% in those with mild dyskaryosis. The range between sites was 34.8–73.3% for borderline cytology, and 73.4–91.6% for mild dyskaryosis. In the single site using both LBC technologies there was no difference in rates between the two technologies. The positive predictive value of an HPV test was 16.3% for CIN2 or worse and 6.1% for CIN3 or worse, although there was considerable variation between sites.

Conclusion:

Triaging women with borderline cytological abnormalities and mild dyskaryosis with HPV testing would allow approximately a third of these women to be returned immediately to routine recall, and for a substantial proportion to be referred for colposcopy without repeat cytology. Variation in HPV-positive rates results in differing colposcopy workload.     

Identification of transmitter systems and learning tag molecules involved in behavioral tagging during memory formation

Long-term memory (LTM) consolidation requires the synthesis of plasticity-related proteins (PRPs). In addition, we have shown recently that LTM formation also requires the setting of a “learning tag” able to capture those PRPs. Weak training, which results only in short-term memory, can set a tag to use PRPs derived from a temporal-spatial closely related event to promote LTM formation. Here, we studied the involvement of glutamatergic, dopaminergic, and noradrenergic inputs on the setting of an inhibitory avoidance (IA) learning tag and the synthesis of PRPs. Rats explored an open field (PRP donor) followed by weak (tag inducer) or strong (tag inducer plus PRP donor) IA training. Throughout pharmacological interventions around open-field and/or IA sessions, we found that hippocampal dopamine D1/D5- and β-adrenergic receptors are specifically required to induce PRP synthesis. Moreover, activation of the glutamatergic NMDA receptors is required for setting the learning tags, and this machinery further required α-Ca²⁺/calmodulin-dependent protein kinase II and PKA but not ERK1/2 activity. Together, the present findings emphasize an essential role of the induction of PRPs and learning tags for LTM formation. The existence of only the PRP or the tag was insufficient for stabilization of the mnemonic trace.     

Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial

BackgroundThe incidence of local recurrence (LR) after conservative surgery for early breast cancer without adjuvant therapy is unacceptably high even with favourable tumours. The aim of this study was to examine the effect of adjuvant therapies in tumours with excellent prognostic features.MethodsPatients with primary invasive breast cancer <2 cm diameter, grade 1 or good prognosis special type, and node negative, treated by wide local excision (WLE) with clear margins were randomised into a 2 × 2 clinical trial of factorial design with or without radiotherapy and with or without tamoxifen. Trial entry was allowed to either comparison or both.FindingsThe actuarial breast cancer specific survival in 1135 randomised patients at 10 years was 96%. Analysis by intention to treat showed that LR after WLE was reduced in patients randomised to radiotherapy (RT) (HR 0.37, CI 0.22-0.61 p < 0.001) and to tamoxifen (HR 0.33, CI 0.15 – 0.70 p < 0.004). Actuarial analysis of patients entered into the four-way randomisation showed that LR after WLE alone was 1.9% per annum (PA) versus 0.7% with RT alone and 0.8% with tamoxifen alone. No patient randomised to both adjuvant treatments developed LR. Analysis by treatment received showed LR at 2.2% PA for surgery alone versus 0.8% for either adjuvant radiotherapy or tamoxifen and 0.2% for both treatments.ConclusionsEven in these patients with tumours of excellent prognosis, LR after conservative surgery without adjuvant therapy was still very high. This was reduced to a similar extent by either radiotherapy or tamoxifen but to a greater extent by the receipt of both treatments.