PKMζ is essential for spinal plasticity underlying the maintenance of persistent pain

<p>Abstract</p> <p>Background</p> <p>Chronic pain occurs when normally protective acute pain becomes pathologically persistent. We examined here whether an isoform of protein kinase C (PKC), PKMζ, that underlies long-term memory storage in various brain regions, also sustains nociceptive plasticity in spinal cord dorsal horn (SCDH) mediating persistent pain.</p> <p>Results</p> <p>Cutaneous injury or spinal stimulation produced persistent increases of PKMζ, but not other atypical PKCs in SCDH. Inhibiting spinal PKMζ, but not full-length PKCs, reversed plasticity-dependent persistent painful responses to hind paw formalin and secondary mechanical hypersensitivity and SCDH neuron sensitization after hind paw capsaicin, without affecting peripheral sensitization-dependent primary heat hypersensitivity after hind paw capsaicin. Inhibiting spinal PKMζ, but not full-length PKCs, also reversed mechanical hypersensitivity in the rat hind paw induced by spinal stimulation with intrathecal dihydroxyphenylglycine. Spinal PKMζ inhibition also alleviated allodynia 3 weeks after ischemic injury in rats with chronic post-ischemia pain (CPIP), at a point when allodynia depends on spinal changes. In contrast, spinal PKMζ inhibition did not affect allodynia in rats with chronic contriction injury (CCI) of the sciatic nerve, or CPIP rats early after ischemic injury, when allodynia depends on ongoing peripheral inputs.</p> <p>Conclusions</p> <p>These results suggest spinal PKMζ is essential for the maintenance of persistent pain by sustaining spinal nociceptive plasticity.</p

EN-BIRTH Data Collector Training - Handbook and Manual

The EN-BIRTH study aims to validate selected newborn and maternal indicators for routine facility-based tracking of coverage and quality of care for use at district, national and global levels. The item contains the EN-BIRTH_Trainer's Manual (14 June 2017) and EN-BIRTH_Training Handbook (23 May 2017)

EN-BIRTH Data Collector Training - Supporting Annexes

The EN-BIRTH study aims to validate selected newborn and maternal indicators for routine facility-based tracking of coverage and quality of care for use at district, national and global levels. The item contains consent forms and participant information, in addition to standard operating procedures (SOP) for adverse clinical events, and managing distress in interviews. The full complement of annex files used during the training can be requested via this site if required

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Copyright @ 2013 Macmillan Publishers Limited. This is the author's accepted manuscript. The final published article is available from the link below.Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.Kay Kendall Leukemia Fund, NIH, Cancer Research UK, Italian Association for Cancer Research and the Foundation for Liver Research

MRSA Infection in Vascular Surgical Patients: The HKL Experience

ABSTRAK Jangkitan Methicillin-resistant Staphylococcus aureus (MRSA) kerap berlaku di kalangan pesakit yang menjalani pembedahan vaskular. Ianya boleh mengakibatkan kehilangan anggota atau kematian. Kami melaksanakan analisa retrospektif terhadap nota pesakit pembedahan vaskular di Hospital Kuala Lumpur untuk tempoh 2 tahun mulai Januari 2005 hingga Disember 2007. Ianya bertujuan mengamati corak jangkitan dan faktor-faktor yang mengakibatkan jangkitan ini. Seramai 999 pesakit menjalani pembedahan vaskular dalam rangkuman jangkamasa kajian ini. Dari jumlah ini, seramai 24 pesakit (2.4%) dikesan terjangkit oleh MRSA. Jangkitan ini didapati terjurus kepada pesakit yang merokok, pesakit diabetes melitus dan mereka yang terdahulunya pernah menjalani pembedahan vaskular. Kebanyakan jangkitan bercorak kemusnahan terhadap luka pembedahan dan berlaku dalam kategori pembedahan kecemasan. Sebanyak 54% dari kes jangkitan berakhir dengan kehilangan anggota atau pengeluaran graf vaskular atau kematian. Jangkitan MRSA mengakibatkan kesan klinikal yang buruk terhadap pesakit yang menjalani pembedahan vaskular. Langkah pencegahan yang intensif diperlukan bagi mengelakkan kesan buruk yang tidak diingini ini. Kata kunci: jangkitan MRSA, pembedahan vaskular ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) infection is important among vascular surgical patients. Its effect can be devastating resulting in limb amputation and mortality. We performed a retrospective patients record analysis to determine the pattern of MRSA infection among vascular surgical patients in Hospital Kuala Lumpur from January 2005 to December 2007. We also attempted to identify the factors associated with poor clinical outcome after such infection. There were 999 patients who underwent vascular surgeries in HKL within the analysis period. Of these 24 patients (2.4%) were detected to have MRSA surgical site infection. The infection was commoner among cigarette smokers, patients with diabetes melitus and those who &amp; Health 2008; 3(2): 294-299 had previous vascular surgery. Most infections occurred in the emergency surgery category and manifested as wound breakdown. Fifty-four percent of the infected patients ended with graft removal, amputations or death. MRSA infection complicating vascular surgery resulted in poor clinical outcome. This serious threat requires intensified preventive measures

EN-BIRTH Data Collection Tools

The EN-BIRTH study aims to validate selected newborn and maternal indicators for routine facility-based tracking of coverage and quality of care for use at district, national and global levels. The item contains the following data collection tools: Register data extraction, Observation checklist (labour and delivery ward), Observation checklist (kangaroo mother care), Patient record verification tools for antenatal corticosteroid administration, Patient record verification tools for antibiotic administration, and the Maternal recall survey

EN-BIRTH Data Collector Training – Training Module material

The EN-BIRTH study aims to validate selected newborn and maternal indicators for routine facility-based tracking of coverage and quality of care for use at district, national and global levels. The item contains PowerPoint slides used for the nine modules of the Data Collector's Training Programme delivered during May and June 2017. Module 1 (introduction) provides an overview of the training syllabus; Module 2 (Registration) helps tracking officers to understand their roles and responsibilities in the project and how to best execute them; Module 3 (Observation: Labour & Delivery) is intended to help Labour & Delivery observers to conduct themselves, and their work, in accordance with project guidelines and training handbook; Module 4 (Observation: Resuscitation - Nepal) covers the function of CCTV cameras and the value of collecting extra observation data from filmed clinical events; Module 5 (Observation: KMC) outlines expectations and practices to be applied by KMC (kangaroo mother care) observers; Module 6 (Data Extraction & Verification) outlines how data collectors should extract and verify register data and record information in the app extraction form in the L&D ward and KMC ward; Module 7 (Maternal Pre-discharge Recall Survey) outlines how to conduct high-quality interviews and administer the maternal pre-discharge recall survey; Module 8 (Supervision) equips supervisors with the skills to be good team managers, ensure team effectiveness and happiness, respond to incidents in the health facility, and monitor data quality; and finally Module 9 (Training Summary) provides a recap of key information taught over the week

Climate change impact and adaptation for wheat protein

Wheat grain protein concentration is an important determinant of wheat quality for human nutrition that is often overlooked in efforts to improve crop production. We tested and applied a 32‐multi‐model ensemble to simulate global wheat yield and quality in a changing climate. Potential benefits of elevated atmospheric CO2 concentration by 2050 on global wheat grain and protein yield are likely to be negated by impacts from rising temperature and changes in rainfall, but with considerable disparities between regions. Grain and protein yields are expected to be lower and more variable in most low‐rainfall regions, with nitrogen availability limiting growth stimulus from elevated CO2. Introducing genotypes adapted to warmer temperatures (and also considering changes in CO2 and rainfall) could boost global wheat yield by 7% and protein yield by 2%, but grain protein concentration would be reduced by −1.1 percentage points, representing a relative change of −8.6%. Climate change adaptations that benefit grain yield are not always positive for grain quality, putting additional pressure on global wheat production

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era