Multiple ipsilateral femoral stress fractures in a patient taking denosumab for osteoporosis-a case report.

This is the first report describing three ipsilateral femoral stress fractures in a patient taking denosumab. INTRODUCTION: Multiple reports of atypical femur fractures (AFF) in patients receiving denosumab have emerged recently. Denosumab is an anti-resorptive agent approved for treatment of osteoporosis. It is a human monoclonal antibody which blocks osteoclast activation, maturation, and function. METHODS: This is a case report of a 74-year-old female patient who sustained three stress fractures of her left femur. RESULTS: The patient healed her fractures after intramedullary nailing of the femur and was able to return to her activities. CONCLUSIONS: High index of suspicion is needed in any patient with osteoporosis on denosumab complaining of thigh or groin pain. Careful examination and radiographic studies of both femurs are warranted if AFF is discovered.

Messenger RNA encoding constitutively active Toll-like receptor 4 enhances effector functions of human T cells.

Adoptive T cell therapy of cancer employs a large number of ex-vivo-propagated T cells which recognize their targets either by virtue of their endogenous T cell receptor (TCR) or via genetic reprogramming. However, both cell-extrinsic and intrinsic mechanisms often diminish the in-vivo potency of these therapeutic T cells, limiting their clinical efficacy and broader use. Direct activation of human T cells by Toll-like receptor (TLR) ligands induces T cell survival and proliferation, boosts the production of proinflammatory cytokines and augments resistance to regulatory T cell (Treg) suppression. Removal of the TLR ligand-binding region results in constitutive signalling triggered by the remaining cytosolic Toll/interleukin-1 receptor (TIR) domain. The use of such TIR domains therefore offers an ideal means for equipping anti-tumour T cells with the arsenal of functional attributes required for improving current clinical protocols. Here we show that constitutively active (ca)TLR-4 can be expressed efficiently in human T cells using mRNA electroporation. The mere expression of caTLR-4 mRNA in polyclonal CD8 and CD4 T cells induced the production of interferon (IFN)-γ, triggered the surface expression of CD25, CD69 and 4-1BB and up-regulated a panel of cytokines and chemokines. In tumour-infiltrating lymphocytes prepared from melanoma patients, caTLR-4 induced robust IFN-γ secretion in all samples tested. Furthermore, caTLR-4 enhanced the anti-melanoma cytolytic activity of tumour-infiltrating lymphocytes and augmented the secretion of IFN-γ, tumour necrosis factor (TNF)-α and granulocyte-macrophage colony-stimulating factor (GM-CSF) for at least 4 days post-transfection. Our results demonstrate that caTLR-4 is capable of exerting multiple T cell-enhancing effects and can potentially be used as a genetic adjuvant in adoptive cell therapy.

Surgical site infection in elderly patients with hip fractures, silver-coated versus regular dressings: a randomised prospective trial.

OBJECTIVE: Surgical site infection (SSI) after hip fracture surgery is a well-known complication with serious consequences for both the patient and the medical system. Silver ion treatment is considered an effective antibacterial agent, however, the use of silver dressing (SD) in the primary prevention of SSIs is controversial. The aims of this study were to compare SD with regular dressing (RD) in the prevention of SSI in elderly patients undergoing surgery for hip fractures, and to compare costs. METHOD: A matched group of 55 patients with hip fractures undergoing surgery with dynamic hip screw, cephalomedullary nail or hemiarthroplasty were randomised to either SD or RD groups. The dressings were applied in the operating theatre, and the patients were followed for one week for clinical signs of infection (discharge, erythema and fever). The RDs were replaced daily. The SDs were not removed for 5-7 days and kept moist. Skin swabs were taken from the wound surface on postoperative day 5-7 for bacterial skin colonisation. RESULTS: The SD (n=31) and RD (n=24) groups were similar in age, sex and comorbidities. Infection signs were seen in two (2/31, 6.4%) of the SD patients compared with 2 (2/24, 8.3%) RD patients (p=1.0). Skin colonisation by bacteria at postoperative day 5-7 was tested in 27 patients: it was higher in the SD group (positive skin swab, 12/19, 63.2%) compared to the RD group (4/8, 50%, p=0.67). The use of SD added ~US$5 (UK ~£3.19) per patient. CONCLUSION: The use of SD was associated with higher costs than RD, but not superior in preventing SSIs in elderly patients undergoing hemiarthroplasty or fixation of hip fractures. SD was also not effective in reducing bacterial skin colonisation following hip fracture and surgery.

Early postoperative dressing removal in hand surgery: Novel concepts for individualized surgical dressing management.

Postoperative dressing protocols after clean surgery without implant vary widely. The purpose of this study was to elucidate whether early postoperative dressing removal is a valid option, as compared to untouched dressing or twice-weekly dressing change approach. A prospective randomized study was conducted on patients who underwent carpal tunnel release (CTR) or trigger finger release (TFR) between January and November 2020. Patients were randomly distributed into 3 groups: surgical dressing untouched until first follow up (SDU); surgical dressing changed twice a week in a health maintenance organization (HMO); and surgical dressing removed at first postoperative day (SDR). Data collected included patient characteristics, pre-and post-operative functional (QuickDASH) and autonomy (Instrumental Activities of Daily Living performance (IADL)) scores, Vancouver scar scale (VSS) and potential complications. Eighty-four patients were included: 28 (33.3%), 29 (34.5%) and 27 (32.1%) in the SDU, HMO and SDR groups, respectively. Deterioration in mean IADL score at 2-week follow-up was statistically significant in the HMO group (mean delta 3.35, p = 0.008). Quick DASH score improved significantly between preoperative and 2-week follow-up values only in the SDU group (mean delta 9.12, p = 0.012). Other parameters, including wound complications, did not differ significantly between groups. Early removal of postoperative dressing and immediate wound exposure was a safe option after CTR and TFR. An untouched bulky dressing correlated with early functional improvement. Finally, iterative dressing change in HMO showed no benefit and led to significant deterioration in early postoperative autonomy. IRB APPROVAL: 0548-18-TLV. LEVEL OF EVIDENCE: I.

Spontaneous infectious discitis in adults.

PURPOSE: In adults, discitis most frequently follows spinal surgery. We report 16 adult patients with spontaneously occurring infectious discitis and compare them with an additional 52 patients abstracted from the literature. Infecting organisms, predisposing factors, imaging modalities, and response to therapy are described. PATIENTS AND METHODS: The medical records of adult patients treated for infectious discitis of a community hospital during the past 10 years were reviewed. Postoperative spine patients and patients with primary osteomyelitis were excluded. Sixteen patients were identified with spontaneous primary infection of the disc space. The particulars of comorbid conditions, infection organisms, site of culture, and response to antibiotic therapy were noted and compared to 52 additional cases of spontaneous discitis reported in the literature since 1980. RESULTS: A wide variety of infecting organisms was identified as causing spontaneous discitis, in contrast to previous reports of both postoperative discitis and spontaneous discitis. Nine of 10 patients with positive disc cultures had negative blood cultures. Appropriate antibiotics were curative in all patients but 1, regardless of the duration of symptoms. Nuclear imaging, computed tomography, and magnetic resonance imaging were all useful, although the last appears to be the most sensitive and specific imaging modality for detecting discitis. CONCLUSIONS: Spontaneous infectious discitis is an uncommon cause of low back pain in adults. Nevertheless, it should be considered in any patient with acute or subacute pain. Elevated acute-phase reactants with appropriate imaging modality suggest the diagnosis. given the wide variety of infecting organisms identified, culture of blood and/or disc for the specific causative organism is critical to successful treatment outcome.

LC/MS determination of the intracellular concentration of two novel aryl phosphoramidate prodrugs of PMPA and their metabolites in dog PBMC.

LC/MS assays were developed to determine the plasma and intracellular concentrations of two aryl phosphoramidate prodrugs of the nucleotide analog 9-[2-R-(phosphonomethoxy)propyl]adenine. LC/MS was used to demonstrate the presence of high concentrations of PMPA in peripheral blood mononucleocytes following oral administration of prodrugs in dogs. High concentrations of PMPA and active metabolite were detected in MT-2 cells incubated with prodrug using an ion-pairing LC/MS assay.

Henoch-Schönlein purpura: a diagnosis not to be forgotten.

Henoch-Schönlein purpura (HSP) is a systemic, generalized vasculitis of unknown etiology thought to be related to an IgA-mediated autoimmune phenomenon. Diagnosis is based on a constellation of physical findings that include the characteristic nonthrombocytopenic petechial or purpuric rash, migratory polyarthralgias, abdominal pain, and renal complications. We report the case of a 19-year-old man with a diagnosis of HSP who had severe abdominal pain and endoscopic documentation of duodenal involvement. Though not clear at presentation, the diagnosis became obvious when the characteristic rash emerged.

Antiphospholipid syndrome: the reality and implications.

A case is made for the existence of a primary antiphospholipid antibody syndrome. This clinical entity can be characterized as including an elevation in titers of antibodies to negatively charged phospholipids, hypercoagulation, thrombocytopenia, and recurrent fetal loss. With further elucidation, the systemic pathologic roles of antiphospholipid antibodies should emerge.

Experimental scrub typhus immunogens: gamma-irradiated and formalinized rickettsiae.

Scrub typhus immunogens were prepared by exposing infected yolk sac suspensions of Rickettsia tsutsugamushi to various doses of gamma radiation. Mouse lethality was abolished at doses greater than 200 krads, whereas immunogenicity of the suspensions, as shown by mouse protection tests, was diminished relatively little by radiation doses in the 200- to 400-krad range. Using a 300-krad gamma dose to provide a safety factor, immunogens were prepared and their protective capacity was contrasted with formalinized scrub typhus immunogens prepared by conventional techniques. Formalinized suspensions afforded mice only partial protection against intraperitoneal challenge with 1,000 50% mouse lethal doses of the virulent homologous strain and no significant protection against similar challenge with an equally virulent heterologous strain. Using the same strains, radiation-inactivated preparations provided 100% protection against 10,000 50% mouse lethal doses of the homologous strain and 70% protection against challenge with the same doses of a heterologous strain. Neither immunogen was a potent stimulator of antibody production as measured by the complement-fixation test. Cell-transfer studies using inbred mice indicated a role for cell-mediated immunity after vaccination with gamma-irradiated immunogens, but no cell-mediated protection could be demonstrated after vaccination with formalin-inactivated rickettsiae.

Effects of temperature on the stability of Rickettsia tsutsugamushi and gamma-irradiated scrub typhus immunogens.

Unirradiated Rickettsia tsutsugamushi and a component of gamma-irradiated Karp immunogen required for homologous immunity were more stable than the immunogen component that elicited heterologous (Kato strain) protection.

Gamma-irradiated scrub typhus immunogens: development and duration of immunity.

The development and duration of immunity to lethal scrub typhus infection was studied in BALB/c mice vaccinated with gamma-irradiated Rickettsia tsutsugamushi, strain Karp. One intraperitoneal injection containing approximately 10(8) 50% mouse lethal doses (MLD(50)) of irradiated organisms elicited an immune response protective against challenge with 10(5) MLD(50) of viable Karp. The same mass of immunogen given in three injections at 5-day intervals increased homologous (Karp strain) protection 25-fold and heterologous (Kato strain) protection 60-fold. Further temporal expansion of the immunization regimen did not increase protection. Subcutaneous vaccination provided significant, but lower, levels of protection than were achieved by intraperitoneal immunization, but the levels of cell-transferable immunity elicited by the two routes were approximately the same. Immunologically specific protection after intraperitoneal vaccination developed rapidly enough to provide resistance against simultaneous challenge with 200 MLD(50) of Karp. Homologous immunity was protective against a 10(6)-MLD(50) challenge 7 days after completion of the three-injection regimen, remained at that level for 3 months, dropped to 10(4) MLD(50) by 9 months, and was effective against a 50-MLD(50) Karp challenge at 12 months. Protection against heterologous challenge was first observed on day 17 and peaked on day 38, when the mice resisted a 10(5)-MLD(50) Kato challenge. Thereafter, heterologous protection waned rapidly and was not significant at 6 months.

Gamma-irradiated scrub typhus immunogens: broad-spectrum immunity with combinations of rickettsial strains.

Scrub typhus immunogens were prepared from Rickettsia tsutsugamushi strains Karp, Kato, Gilliam, Kostival, and Buie by exposing frozen infected yolk sac suspensions to 300 krad of gamma radiation. Mouse protection tests showed that each of the irradiated immunogens protected C3H/HeDub mice against high challenge levels of Karp and Gilliam, but that none of these single-strain immunogens were capable of protecting against all five of the challenge strains. Broad-spectrum protection was achieved by using combinations of three strains of irradiated rickettsiae in a vaccination regimen of three injections at 5-day intervals. A comparison of vaccination efficacy employing three such combinations (Karp-Gilliam-Kato, Karp-Kostival-Kato, and Buie-Kostival-Kato) indicated that both sequential administration of strains on successive vaccination days and multiple injections of trivalent mixtures produced protective responses superior to those obtained with single-strain immunogens. Trivalent mixtures of rickettsiae exhibited a striking synergistic effect on the immune response of C3H/HeDub mice and elicited a protective response against Kato challenge that could not be obtained with any single-strain immunogen. Mice vaccinated with the trivalent Karp-Gilliam-Kato immunogen resisted challenge with more than 10(3) 50% mouse lethal doses of Karp and Gilliam for 12 months, and were resistant to similar levels of challenge with Kato and Buie for 6 months.

Gamma-irradiated scrub typhus immunogens: analysis for residual, replicating rickettsiae.

Scrub typhus immunogens that received inadequate gamma radiation contained residual, viable rickettsiae. The presence of these organisms in the host was masked by the rapid immune response elicited by the large number of inactivated rickettsiae. Transfer of homogenized spleen cells from immunized mice to normal syngeneic recipients provided a sensitive technique for the detection of these viable, replicating organisms.

Decline of maternal antibodies to plague in Norway rats.

The decline of maternal antibodies to the fraciton I antigen of Yersinia pestis was investigated in newly weaned Rattus norvegicus obtained from dams vaccinated with strain EV76(51F) of Y. pestis. IHA titre decreased by 50% each 7-3 days and CF titre declined 50% each 10-0 days in young rats. An analysis of available data indicated that maternal IHA and CF antibodies could persist to 3 months of age. Therefore, positive serologic reactions in young R. norvegicus, detected in the course of serological surveys, could be the result either of active immunization after exposure to the plague bacillus or of transient passive immunization (i.e. maternal antibody).

Involuntary commitment and the treatment process: a clinical perspective.

The serious question of involuntary hospitalization at this point in history is properly referred to due process in court. While numerous studies have addressed the decisions, statistics and outcomes in this area, insufficient attention has been paid to how the clinician may productively incorporate the clinical experience mobilized by the procedure into the therapeutic work. The authors suggest that the issues raised include maintenance of the alliance, responsibility, dependence, limit-setting, the subjective experience of the process, and the problem of counter-transference. They indicate how the various aspects of commitment may be explored aso as to yield maximal therapeutic benefit, and maintain the alliance during the conflicts of an adversary procedure.

Postpartum hemolytic uremic syndrome associated with antiphospholipid antibodies. A case report and review of the literature.

Postpartum hemolytic uremic syndrome (HUS) is described in a woman with a history of spontaneous abortions and both circulating lupus anticoagulant and anticardiolipin antibody (ACA). After termination of her pregnancy because of severe preeclampsia, ACA blood levels increased simultaneously with the onset of a microangiopathic process associated with severe hypertension and renal failure. Plasma exchange resulted in a rapid decline in ACA levels and immediate improvement in her clinical condition. This case strongly suggests an important causal relationship between ACA and postpartum HUS. The possible mechanisms of ACA-related postpartum HUS and the potential role of plasmapheresis in its treatment are reviewed and discussed.

Role of elastic fibers in cooling-induced relaxation.

The objective of this work was to confirm the main role of elastic fibers in differing responses of certain vessels during cooling from 37 to 8 degrees C. Previous results have shown that the nature of the vessel (conduit vessel vs muscular vessel) determines the different behavior (dilatation vs contraction) of isolated vessel segments when temperature decreases from 37 to 8 degrees C. In this work, it has been demonstrated that vessels with a great amount of elastic fibers show a dilatation when cooling. On the other hand, muscular vessels with fewer elastic fibers, such as the renal artery, undergo a contraction. The output of calcium from intracellular stores causes contraction of the renal artery during cooling. In this vessel, vasodilatation occurs only when mechanisms of smooth muscle contraction are inactive, as is the case with vessels that have undergone a cold storage period of 48 h. The results presented in this work confirm that there are two main effects, which directly depend on the vessel origin. In conduit arteries, the decrease of temperature induces a vascular relaxation, dependent on the elastic component of the vessel wall. In muscular vessels, the predominant effect is cooling-induced contraction due to an increase of intracellular calcium. This cooling-induced contraction needs the vessel to be in optimal conditions with an active metabolism of the muscular cells. These results are a crucial issue in the sense of explaining several biomedical mechanisms where hypothermia is implicated. The type of vessel implicated in procedures, such as isolated organ perfusion, extracorporeal circulation, and bypass surgery, must be taken into account.

Host defenses in experimental scrub typhus: effect of chloramphenicol.

The effect of chloramphenicol treatment on the development of immunity to scrub typhus in mice was studied. Chemotherapy was administered either shortly before infection and for 14 days thereafter (group I), or from 7 to 21 days postinfection (group II). Although the full course of either regimen resulted in complete protection of the mice against subsequent challenge with the homologous strain of Rickettsia tsutsugamushi, initiation of chemotherapy at 7 days postinfection resulted in more rapid development of immunity against both the original infection and subsequent challenge. In both treatment groups, a 1- to 2- day hiatus was observed between immunity to challenge in the treated animal and the ability to transfer this immunity to syngeneic recipients with lymphocyte-enriched spleen cells. Similarly, complement-fixing antibodies were not detectable until shortly after the animals were able to resist challenge. These data supported the conclusion that the rickettsiostatic effect of chloramphenicol allows the infected animal time to mount an effective immune response and, further, that initiation of chemotherapy early in the infection may delay development of this response.