Murine osteoblasts respond to LPS and IFN-γ similarly to macrophages

Osteoblasts are bone-forming mesenchymal cells, while macrophages are cells of hematopoietic origin responsible for innate immunity. Lipopolysaccharide (LPS) can induce tolerance in macrophages, whereas interferon (IFN)-γ can activate macrophages to produce cytokines, exert bactericidal effects, and present antigens. In this study, we examined such macrophagic phenotypes regulated by LPS and IFN-γ in murine osteoblasts. In both primary calvarial osteoblasts and osteoblastic MC3T3-E1 cells, LPS pretreatment resulted in reduced production of IL-6 in response to a subsequent LPS stimulation or to Salmonella infection, indicating the existence of LPS-induced tolerance in osteoblasts. Furthermore, IFN-γ treatment of MC3T3-E1 cells resulted in both enhanced IL-6 production in response to LPS and upregulation of major histocompatibility complex class II (MHC II). Following infection, Salmonella-containing vacuoles (SCVs) were formed in MC3T3-E1 cells, and IFN-γ pretreatment enhanced bactericidal effects on intracellular Salmonella. Taken together, these observations indicate that osteoblasts can exhibit a subset of phenotypes reminiscent of macrophages in the course of bacterial infection.     

Introduction to Prostate Cancer and Prostatic Diseases

Prostate Cancer and Prostatic Diseases covers all aspects of prostatic diseases, in particular prostate cancer, the subject of intensive basic and clinical research worldwide. The journal also reports on     

HIV and tuberculosis – science and implementation to turn the tide and reduce deaths

Introduction

Every year, HIV-associated tuberculosis (TB) deprives 350,000 mainly young people of productive and healthy lives. People die because TB is not diagnosed and treated in those with known HIV infection and HIV infection is not diagnosed in those with TB. Even in those in whom both HIV and TB are diagnosed and treated, this often happens far too late. These deficiencies can be addressed through the application of new scientific evidence and diagnostic tools.

Discussion

A strategy of starting antiretroviral therapy (ART) early in the course of HIV infection has the potential to considerably reduce both individual and community burden of TB and needs urgent evaluation for efficacy, feasibility and broader social and economic impact. Isoniazid preventive therapy can reduce the risk of TB and, if given strategically in addition to ART, provides synergistic benefit. Intensified TB screening as part of the “Three I''s” strategy should be conducted at every clinic, home or community-based attendance using a symptoms-based algorithm, and new diagnostic tools should increasingly be used to confirm or refute TB diagnoses. Until such time when more sensitive and specific TB diagnostic assays are widely available, bolder approaches such as empirical anti-TB treatment need to be considered and evaluated. Patients with suspected or diagnosed TB must be screened for HIV and given cotrimoxazole preventive therapy and ART if HIV-positive. Three large randomized trials provide conclusive evidence that ART initiated within two to four weeks of start of anti-TB treatment saves lives, particularly in those with severe immunosuppression. The key to ensuring that these collaborative activities are delivered is the co-location and integration of TB and HIV services within the health system and the community.

Conclusions

Progress towards reducing HIV-associated TB deaths can be achieved through attention to simple and deliverable actions on the ground. John Donne, Meditation XVII, Devotions upon Emergent Occasions: … any mans death diminishes me because I am involved in Mankinde; And therefore never send to know for whom the bell tolls; it tolls for thee ….     

When and how to operate on thoracic and lumbar spine fractures?

Purpose

To discuss when and how to operate on thoracic and lumbar spine fractures.

Patients and methods

We retrospectively studied 77 consecutive patients with thoracic and lumbar spine fractures treated from 2000 to 2011; 28 patients experienced high-energy spinal trauma and 49 low-energy spinal trauma. Mean follow-up was 5 years (1–11 years). Surgical treatment was done in 15 patients with neurological deficits, and in 16 neurologically intact patients with fractures–dislocations, burst fractures and fractures with marked deformity. Non-surgical treatment was done in 46 neurologically intact patients with simple fracture configurations. Clinical and imaging examination and the Oswestry Disability Index (O.D.I.) questionnaire were obtained.

Results

All patients treated surgically maintained spinal alignment; patients with long fusion maintained the best alignment; however, they experienced back stiffness and moderate low back pain. Patients with combined posterior fusion and kyphoplasty experienced earlier recovery and improved sagittal correction. Mean O.D.I. was 22.4 and 14.2 % at 3 and 12 months postoperatively. Thirty six (78 %) patients treated non-surgically were asymptomatic, 22 (48 %) experienced mild residual kyphosis, 10 (22 %) developed marked deformity during their follow-up and were finally operated; mean O.D.I. was 28.6 and 12.1 % at 3 and 12 months. No difference in O.D.I. was observed between patients who had surgical and non-surgical treatment.

Conclusions

Progressive neurological deficits and/or mechanical instability of the spine are absolute indications for early surgical treatment. Younger patients with high-energy spinal trauma, unstable fractures and neurological deficits should be treated surgically in order to provide optimum conditions for neurologic recovery, early mobilization and possibly ambulation. Most cases can be adequately operated through a posterior only surgical approach; an anterior or combined approach is usually indicated for burst and thoracic spine fractures. Postoperative complications, more common infection and neurological deterioration may occur. Elderly, neurologically intact patients with low-energy, stable spinal fractures without marked spinal deformity may be successfully treated conservatively. Most of these patients will do well; however, follow-up for progressive posttraumatic deformity is required.     

Damage- and pathogen-associated molecular patterns and alarmins: keys to sepsis?

The concept that sepsis is the result of an uncontrolled inflammatory response of the host's innate immune system towards invading pathogens has recently been challenged. Evidence is accumulating that, in addition, host-derived alarm molecules are released during sepsis- and trauma-associated cell death, thus triggering the host's immune response. The identification and characterization of exogenous as well as endogenous danger molecules allowed significant advances in our understanding of the pathophysiology of sepsis and may provide potential targets for therapeutic interventions.     

Why and how to promote peritoneal dialysis?

The prevalence of peritoneal dialysis in France remains one of the lowest in Europe in spite of official recommendations in 2008. Progress in peritoneal catheter placement and a good knowledge of the management of catheter complications are essential. A more frequent use of biocompatible solutions should achieve a better preservation of the peritoneal membrane. Such physiological peritoneal fluids seem to decrease morbidity and mortality. Best peritoneal dialysis indications are mainly young patients waiting for a kidney transplantation, old patients without malnutrition and patients with cardiac insufficiency. Objective and complete information dedicated to both peritoneal dialysis and hemodialysis is necessary, even for patients seen in emergency or unplanned or late referral patients. A pre-end-stage renal disease education program has to be mandatory. Non-medical obstacles, mainly financial, are still common so that economic incitations are necessary for the development of peritoneal dialysis. A university formation of nephrologists is now available.     

Trauma and motorcyclists: born to be wild, bound to be injured?

BACKGROUND: Regrettably motorcyclists frequently suffer related significant injuries. Doctors who manage trauma will encounter victims of motorcycle accidents and many aspects of care are unique to these patients due to the protective and performance enhancing equipment used by motorcyclists. This review examines the patterns of major injuries suffered by motorcyclists, the unique aspects of airway, circulatory and spine management, and suggests some interventions, which may allow primary injury prevention for the future. DATA SOURCE: Literature searches of the PubMed, EMBASE and Cochrane library with hand searches and author's experience. INTERVENTIONS: None. DATA SYNTHESIS AND CONCLUSIONS: The airway and (cervical and thoracolumbar) spine cannot be managed effectively in the helmeted patient with a speed hump in place and intubation by direct laryngoscopy is almost impossible with a speed hump in place. Helmets should be removed and the speed hump cut from the leathers. Leathers act as fracture splints, particularly for pelvis and lower extremities. Removal or extensive cutting away of the lower portion of leathers should be considered as part of "circulation", and only take place in a medical facility and in anticipation of circulatory deterioration. Motorcyclists sustaining thoracic spinal damage more frequently than cervical and spinal fractures at multiple levels are common. Back protectors are used commonly and these may be left in situ for extrication on a spinal board, but they should be removed in-hospital to allow full assessment. Injury prevention will require coordinated research and development of a number of key pieces of equipment and design in particular helmets, speed humps and clothing/textiles. In managing the injured motorcyclist in the pre or in-hospital settings, health professionals require greater awareness of the implications of such devices, which at the present time appears largely restricted to motorcycling enthusiasts.     

How much are patients willing to pay to avoid postoperative nausea and vomiting?

Postoperative nausea and vomiting (PONV) are unpleasant experiences. However, there is no drug that is completely effective in preventing PONV. Whereas cost effectiveness analyses rely on specific health outcomes (e.g., years of life saved), cost-benefit analyses assess the cost and benefit of medical therapy in terms of dollars. We hypothesized that patients were willing to pay for a hypothetical new drug that would eliminate PONV. Eighty elective day surgical patients using general anesthesia participated in the study. After their recovery in the postanesthetic care unit, they were asked to complete an interactive computer questionnaire on demographics, the value of avoiding PONV, and their willingness to pay for an antiemetic. Patients were willing to pay US$56 (US$26--US$97; median, 25%--75%) for an antiemetic that would completely prevent PONV. Patients who developed nausea (n = 21; 26%) and vomiting (n = 9; 11%) were willing to pay US$73 (US$44--US$110) and $100 (US$61--US$200; median, 25%--75%), respectively (P < 0.05). Seventy-six percent of patients considered avoiding postoperative nausea and 78% of patients considered avoiding vomiting as important (> or = 50 mm on a 0--100-mm visual analog scale). Nausea or vomiting in the postanesthetic care unit, greater patient income, previous history of PONV, more importance placed on avoiding nausea and vomiting, increasing age, and being married are independent covariates that increase the willingness to pay estimates. Patients associated a value with the avoidance of PONV and were willing to pay between US$56 and US$100 for a completely effective antiemetic.     

Acute Symptomatic Seizures and Provoked Seizures: to Treat or Not to Treat?

Purpose of review

Acute symptomatic and provoked seizures by definition occur in close proximity to an event and are considered to be situational. The treatment implications and likelihood of recurrence of acute symptomatic and provoked seizures differ from unprovoked seizures. In this article, the authors review the literature on acute symptomatic and provoked seizures with regard to therapeutic approach and risk of recurrence.

Recent findings

In the acute period, patients who suffer from acute symptomatic and provoked seizures have higher rates of morbidity and mortality. Patients with acute symptomatic seizures in the setting of certain conditions including subdural hemorrhage, traumatic penetrating injuries, cortical strokes, neurocysticercosis, venous sinus thrombosis, and viral encephalitis have a higher rate of seizure recurrence although the rate of recurrence of seizures is less than that of patients with unprovoked seizures.

Summary

In patients with acute symptomatic and provoked seizures, short-term treatment with anti-seizure medications is appropriate given the higher morbidity and mortality in the acute phase of illness. In patients with acute symptomatic seizures with persistent epileptiform activity on EEG and structural changes on imaging, longer-term treatment (i.e., a few months as opposed to 1 week) with anti-seizure medications can be considered due to high risk of seizure recurrence. If a patient subsequently has an unprovoked seizure, there is yet a higher risk of recurrence of seizures and likelihood of the development of epilepsy. In these patients, long-term seizure treatment can be considered, keeping in mind that although anti-seizure treatment may reduce risk of seizure recurrence in the short-term, it does not appear to influence long-term seizure remission rates.

     

Human nucleus pulposus cells react to IL-6: independent actions and amplification of response to IL-1 and TNF-α

STUDY DESIGN.: Human nucleus pulposus cells were activated with IL-6 plus IL-6 soluble receptor (sR) in the presence or absence of IL-1β or TNF-α. Cell production of factors modulating the anabolic/catabolic balance of the disc and proteoglycan synthesis were determined. OBJECTIVE.: To evaluate NP cell response to exogenous IL-6, and how IL-6 modulates IL-1 and TNF-α actions in these cells. SUMMARY OF BACKGROUND DATA.: Interleukin-6 (IL-6) is produced by cervical and lumbar herniated discs and is associated with neurological symptoms of intervertebral disc degeneration. It upregulates catabolic gene expression and downregulates matrix protein gene expression in chondrocytes. However, no studies have evaluated the effects of IL-6 on disc nucleus pulposus (NP) cells. METHODS.: NP cells from degenerated human discs were expanded in monolayer, maintained in alginate bead culture, and activated with IL-6 plus IL-6 soluble receptor (sR), in the presence or absence of IL-1β or TNF-α. Conditioned media was collected and analyzed for nitrite, PGE-2, TIMP-1, MMP-3, VEGF, and IL-8. Proteoglycan synthesis was assayed as S-sulfate incorporation normalized to DNA content and relative gene expression measured by rtPCR. RESULTS.: IL-6 + sR decreased collagen and aggrecan message, proteoglycan synthesis, and exacerbated the downregulation of proteoglycan synthesis effected by IL-1. PGE-2 synthesis was increased by IL-6 + sR, as was the induction of COX-2 mRNA. IL-6 + sR also enhanced IL-1 and TNF-α stimulated synthesis of PGE-2. IL-6 + sR induced MMP-3 approximately twofold and increased gene expression and synthesis in cells exposed to IL-1 and TNF-α. MMP-13 induction by TNF-α was also potentiated by IL-6 + sR. IL-6 + sR induced IL-6 gene expression and increased that stimulated by TNF-α fourfold. CONCLUSION.: The results suggest maneuvers to diminish IL-6 production in the disc could provide some protection against the adverse effects of IL-1 and TNF-α, thus, helping preserve disc composition, structure, and function.     

‘Renal hypersensitivity’ to inulin and IgA nephropathy

Hypersensitivity to inulin (polyfructan) is a rare event; two cases of food allergy and some patients presenting with allergy and hypersensitivity after inulin infusion have been reported. An 11-year-old boy suffering from severe immunoglobulin (Ig)A nephropathy (IgAN) experienced both anaphylactic reaction and concomitant relapse of his nephropathy following inulin infusion, used for measuring glomerular filtration rate (GFR) 2 years after the appearance of his initial symptoms. Pruritus, wheezing and cough were observed during a first renal function test; results of prick and intradermal tests were negative for inulin. The patient presented with pallor, asthenia and oliguria when a second inulin infusion was performed under dexchlorpheniramine, leading to the immediate cessation of the infusion. He was readmitted 2 days later because of fatigue and nausea related to acute renal failure. A drug-induced acute interstitial nephritis was first suspected. However, due to the presence of macroscopic haematuria and proteinuria, a renal biopsy was performed and showed acute proliferative relapse of IgAN. The underlying mechanism of inulin hypersensitivity is not well known. We can hypothesize that inulin had activated the innate immune system. Inulin may, thus, have been the initiating event of the renal relapse, acting like an infection, in a patient with IgA-mediated immunological dysregulation.