HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling

Peripheral neuropathic pain induced by the chemotherapeutic cisplatin can persist for months to years after treatment. Histone deacetylase 6 (HDAC6) inhibitors have therapeutic potential for cisplatin-induced neuropathic pain since they persistently reverse mechanical hypersensitivity and spontaneous pain in rodent models. Here, we investigated the mechanisms underlying reversal of mechanical hypersensitivity in male and female mice by a 2 week treatment with an HDAC6 inhibitor, administered 3 d after the last dose of cisplatin. Mechanical hypersensitivity in animals of both sexes treated with the HDAC6 inhibitor was temporarily reinstated by a single injection of the neutral opioid receptor antagonist 6β-naltrexol or the peripherally restricted opioid receptor antagonist naloxone methiodide. These results suggest that tonic peripheral opioid ligand-receptor signaling mediates reversal of cisplatin-induced mechanical hypersensitivity after treatment with an HDAC6 inhibitor. Pointing to a specific role for δ opioid receptors (DORs), Oprd1 expression was decreased in DRG neurons following cisplatin administration, but normalized after treatment with an HDAC6 inhibitor. Mechanical hypersensitivity was temporarily reinstated in both sexes by a single injection of the DOR antagonist naltrindole. Consistently, HDAC6 inhibition failed to reverse cisplatin-induced hypersensitivity when DORs were genetically deleted from advillin⁺ neurons. Mechanical hypersensitivity was also temporarily reinstated in both sexes by a single injection of a neutralizing antibody against the DOR ligand met-enkephalin. In conclusion, we reveal that treatment with an HDAC6 inhibitor induces tonic enkephalin-DOR signaling in peripheral sensory neurons to suppress mechanical hypersensitivity.SIGNIFICANCE STATEMENT Over one-fourth of cancer survivors suffer from intractable painful chemotherapy-induced peripheral neuropathy (CIPN), which can last for months to years after treatment ends. HDAC6 inhibition is a novel strategy to reverse CIPN without negatively interfering with tumor growth, but the mechanisms responsible for persistent reversal are not well understood. We built on evidence that the endogenous opioid system contributes to the spontaneous, apparent resolution of pain caused by nerve damage or inflammation, referred to as latent sensitization. We show that blocking the δ opioid receptor or its ligand enkephalin unmasks CIPN in mice treated with an HDAC6 inhibitor (latent sensitization). Our work provides insight into the mechanisms by which treatment with an HDAC6 inhibitor apparently reverses CIPN.     

Long-term outcome of superficialis-to-profundus tendon transfer in patients with clenched fist due to spastic hemiplegia

Background. Spastic hemiplegia is a common feature after stroke, which can result in a clenched fist deformity with secondary hygienic problems and pain. Operative treatment can improve these problems, although literature about its long-term effects is lacking.

Purpose. To determine whether Superficialis-to-Profundus tendon (StP-) transfer procedure leads to permanent improvement of hygiene and reduction of pain in patients with clenched fist due to spastic hemiplegia following stroke.

Method. Patients who underwent a StP-transfer in 2003 – 2005 were evaluated on skin condition, upper extremity joint mobility, resting position and muscle tone and with VAS scores on hygiene maintenance and pain in the hand.

Results. Six patients (mean age 54 years; duration after stroke 10 years) were included. Indications to operate were hygienic problems only (3) or combined with pain (3). The average follow-up period was 19 months. After 6 weeks of post-operative splinting, no standard follow-up was applied. Serious post-operative complications were not reported. At follow-up no hygienic problems were present and pain was decreased in all except one patient. All hands could passively be fully opened. In resting position, flexion was seen in the MCP-joints (60 – 90°). Muscle tone was raised in flexors of the wrist and fingers and m. adductor pollicis (Ashworth 1 – 2). Given the same pre- and post-operative circumstances, all patients would agree to have the surgery over again.

Conclusion. Even 19 months after the StP-transfer for clenched fist, all operated hands could still be fully opened and there was a permanent improvement of hygiene and pain reduction.     

Shared Sanitation versus Individual Household Latrines in Urban Slums: A Cross-Sectional Study in Orissa,India

A large and growing proportion of the global population rely on shared sanitation facilities despite evidence of a potential increased risk of adverse health outcomes compared with individual household latrines (IHLs). We sought to explore differences between households relying on shared sanitation versus IHLs in terms of demographics, sanitation facilities, and fecal exposure. We surveyed 570 households from 30 slums in Orissa, India, to obtain data on demographics, water, sanitation, and hygiene. Latrine spot-checks were conducted to collect data on indicators of use, privacy, and cleanliness. We collected samples of drinking water and hand rinses to assess fecal contamination. Households relying on shared sanitation were poorer and less educated than those accessing IHLs. Individuals in sharing households were more likely to practice open defecation. Shared facilities were less likely to be functional, less clean, and more likely to have feces and flies. No differences in fecal contamination of drinking water or hand-rinse samples were found. Important differences exist among households accessing shared facilities versus IHLs that may partly explain the apparent adverse health outcomes associated with shared sanitation. As these factors may capture differences in risk and promote sanitary improvements, they should be considered in future policy.     

Bacterial cholangitis causing secondary sclerosing cholangitis: A case report

Background  

Although bacterial cholangitis is frequently mentioned as a cause of secondary sclerosing cholangitis, it appears to be extremely rare, with only one documented case ever reported.     

Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF

Recombinant human interleukin-5 (rhIL-5), in either liquid or semi- solid cultures, selectively induced eosinophil production from normal human bone marrow, with no activity on other cell lineages. The time course of eosinophil production induced by murine IL-5, rhIL-3, and rh granulocyte-macrophage colony stimulating factor (GMCSF) was similar to rhIL-5. The rate of eosinophil maturation in vitro was independent of the stimulating cytokine, mature eosinophils being produced after 4 to 5 weeks in liquid culture with each of these cytokines. The eosinophils produced in response to each cytokine were morphologically indistinguishable, and had the ultrastructural features of maturity except that the electron-dense material in the granules had not formed into crystalline cores. Neither rhIL-1 nor rhIL-6 alone, or in combination with rhIL-5 or rhIL-3, induced eosinophil differentiation or proliferation under the conditions used. rhIL-3 and rhGMCSF induced more eosinophil colonies than rhIL-5, rhIL-5 had an additive, not synergistic, effect on eosinophil colony production when combined with either rhIL-3 or rhGMCSF, suggesting that rhIL-5 stimulates a smaller and possibly different population of eosinophil progenitors. However, rhIL-5 induced the greatest eosinophil production in liquid cultures, suggesting that although it may act on a smaller population of precursors, it is able to stimulate more proliferative steps than either rhIL-3 or rhGMCSF.     

The diagnostic value of the fibrinogen/fibrin fragment E antigen assay in clinically suspected deep vein thrombosis

We have evaluated the fibrinogen/fibrin fragment E antigen assay as a diagnostic test in patients with clinically suspected venous thrombosis by comparing the results of this assay with venography in 272 patients. The result of the fragment E antigen assay was elevated in 79 of 80 patients with positive venograms for recent venous thrombosis (sensitivity 99%) and within the normal range in 161 of 192 patients with normal venograms (specificity 84%). The fragment E assay was also evaluated in 130 medical and surgical controls without evidence of venous thrombosis by leg scanning and the test was found to be relatively nonspecific. However, in the patient group under study, a correct clinical diagnosis of no thrombosis, based on a normal fragment E result, was made in 161 of 162 cases (negative predictive value of 99%). Therefore, a normal test result effectively excludes a diagnosis of venous thrombosis in clinically symptomatic patients. The assay, as currently performed, is technically demanding and takes 24 hr to complete. Therefore, it will have to be simplified before it can be applied to clinical practice.