Procalcitonin (PCT) and C-reactive Protein (CRP) as severe systemic infection markers in febrile neutropenic adults

Background  

Procalcitonin (PCT) is an inflammatory marker that has been used as indicator of severe bacterial infection. We evaluated the concentrations of PCT as a marker for systemic infection compared to C-reactive protein (CRP) in patients neutropenic febrile.     

Identification of residues in the first and fourth helices of human granulocyte-macrophage colony-stimulating factor involved in biologic activity and in binding to the alpha- and beta-chains of its receptor

Residues within the first and fourth helices of human granulocyte- macrophage colony-stimulating factor (hGM-CSF) were analyzed for their role in biologic activity and interaction with the alpha- and beta- chains of the hGM-CSF receptor. Within the first helix substitution of the surface residues Glu14, Asn17, Gln20, Arg23, Arg24, and Asn27 or the buried residues Ala18, Leu25, and Leu28 did not significantly impair bioactivity or receptor binding. Substitutions at the buried residues Ala22 and Leu26 had intermediate bioactivity. However, substitutions of the surface residue Glu21 or the buried residue Ile19 reduced the relative bioactivity of the analogues to as little as 0.45% and 0.3%, respectively. Substitution of the charged surface residues of the fourth helix showed that substitution at Glu104, Lys107, and Lys111 had no significant effect on bioactivity, but substitution at Glu108 and Asp112 reduced the potency of the analogues to 34% and 7%, respectively. Receptor binding studies showed that, whereas Glu21 is the critical residue for binding to the hGM-CSF-receptor beta-chain, Asp112 is likely to be involved in binding to the GM-CSF-receptor alpha- chain. These results establish the relative contribution of residues in the first and fourth helices for GM-CSF bioactivity and receptor binding, and support a model where the fourth helix of GM-CSF interacts with the alpha-chain, and the first helix with the beta-chain of the GM- CSF receptor.     

Recombinant human interleukin-3 and granulocyte-macrophage colony- stimulating factor show common biological effects and binding characteristics on human monocytes

Two human hemopoietic growth factors involved in monocytopoiesis, interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were studied for their ability to stimulate blood monocytes and to bind to the monocyte membrane. Both cytokines maintained monocyte/macrophage numbers during long-term culture and increased cell size as compared with controls. Effects on cell numbers were present at low cytokine concentrations (6 to 20 pmol/L), whereas enhanced 3H-thymidine incorporation was observed only at higher concentrations (greater than or equal to 60 pmol/L). Autoradiographic studies showed only 1% to 3% of stimulated monocytes with nuclear grains. These results suggest that the primary mechanism for IL-3 and GM-CSF-induced maintenance of monocyte/macrophage numbers in humans is through an effect on cell survival. Surface receptors for both IL-3 and GM-CSF were studied by using 125I-labeled recombinant human (rh) cytokines and performing Scatchard analyses. Both cytokines showed curvilinear Scatchard plots, and computer analyses favored a two-site binding model. High-affinity binding data for 125I rhIL-3 (Kd 7.7 to 38.2 pmol/L; receptor number/cell 95 to 580) and for 125I rhGM-CSF (Kd 4.7 to 38.9 pmol/L; receptor number/cell 8 to 67) show similar binding affinities for the two cytokines but a lower receptor number/cell for 125I rhGM-CSF. Low-affinity binding characteristics for 125I rhIL-3 (Kd 513 to 939 pmol/L; receptor number/cell 179 to 5,274) and for 125I rhGM- CSF (Kd 576 to 1,120 pmol/L; receptor number/cell 130 to 657) show a similar pattern for the two cytokines. Specificity of 125I rhIL-3 and 125I rhGM-CSF binding to monocytes was established by the ability of the homologous cytokine to inhibit binding and the inability of a range of other cytokines to compete at 100-fold excess molar concentration. It is important, however, that binding of 125I rhIL-3 was partially inhibited by rhGM-CSF and that rhIL-3 partially inhibited binding of 125I rhGM-CSF to the monocyte membrane under conditions shown to prevent receptor internalization. The degree of inhibition varied between 25% and 80% in different experiments, and quantitative inhibition experiments showed that 1,000-fold excess concentrations of competitor failed to inhibit binding of the heterologous ligand completely. These results demonstrate that human IL-3 and GM-CSF have similar effects on growth and survival of human monocytes in vitro and suggest that these and other common biological effects may be mediated either through a common receptor or through distinct receptors associated on the monocyte membrane.     

Effect of an implantable cardioverter defibrillator with atrial detection and shock therapies on patient-perceived,health-related quality of life

Background

This study used a device (DDD implantable cardioverter defibrillator [ICD]) capable of delivering pacing and shock therapies to restore normal sinus rhythm in patients with atrial tachycardias or atrial fibrillation (AF). The purpose of this study was to assess the effect of the device on patient-perceived, health-related quality of life (QOL).

Methods

The DDD ICD was implanted in 267 patients with drug refractory, symptomatic AF from 45 centers across Europe, the United States, and Canada. Patients completed self-reported, validated QOL assessments at baseline and at 3- and 6-month follow-up visits (The Medical Outcomes Short Form 36 [SF-36] and the Symptom Checklist [SCL]).

Results

The mean age of the study group was 62 ± 12 years, and 73% of the patients were male. A total of 150 patients completed SF-36 assessments, and 138 patients completed SCL assessments at all 3 times. Baseline scores were more impaired (P < .05) on most SF-36 scales compared with norms for a general population, but were similar to a comparison group of patients with AF who were referred to tertiary care centers. The role-physical, physical functioning, vitality, mental health, and social functioning scales all improved significantly with time (all P < .04). Similarly, symptom frequency and severity (SCL) also improved significantly from baseline to 6 months (both P < .01). Shock therapy was delivered in 86 of the 150 patients (57%) with complete SF-36 evaluations. There was no evidence that receiving shocks decreased the relative improvement in QOL associated with implantation of the device.

Conclusions

In a 6-month period, QOL improves after implantation of a DDD ICD with atrial shock and pacing therapies. These improvements were not attenuated by receipt of shocks.     

Restriction of cell lysis by homologous complement: I. An analysis of membrane attack complex formation on target membranes

The hemolytic efficiency and binding of C9 to homologous and heterologous erythrocytes was evaluated by using a standardized passive sensitization procedure to prepare antigen- and antibody-coated erythrocytes (EA) and human serum for lysis. Heterologous bovine EA were readily lysed by human serum, whereas human EA were quite resistant to lysis. Human EA bound as many C8 and C9 molecules per cell as bovine EA when incubated under identical conditions, but four times as much bound C9 was required to lyse an equal number of human EA compared with bovine EA. The susceptibility of human erythrocytes did not increase when increased volumes of undiluted human serum were used although C9 binding increased to as much as 100,000 molecules per cell. Sodium dodecyl sulfate-resistant polymerized C9 (poly(C9)) was detected on both lysed ghosts and unlysed EA bearing complement proteins C1 through C9 (EAC1-9) after incubation with undiluted human serum; however, the ratio of poly(C9) to monomeric C9 was higher on unlysed cells than on ghosts. Although bovine and human EA bound equal amounts of human C9 at the end point, the rate of lysis and C9 uptake was slower on homologous cells. The rate-limiting step occurred before C9 binding and lysis because the rates of lysis and C9 binding were equal on homologous and heterologous EAC1-8 targets, but the extent of lysis of homologous cells was still lower than lysis of heterologous cells. Human erythrocytes lose restriction against homologous hemolysis during storage in autologous plasma or in isotonic buffers.     

Precision of navigated and conventional open-wedge high tibial osteotomy in a cadaver study

High tibial osteotomy (HTO) is an established treatment option for isolated medial osteoarthritis in young and active patients. One important factor for success of this procedure is the degree of correction of the weight-bearing line. Computer-assisted navigation systems are believed to improve the precision of axis correction through intraoperative real-time monitoring. This study investigates the precision of correction of the weight-bearing line in open-wedge HTO with and without a navigation system.Nineteen legs of well-preserved human cadaver were randomly assigned to navigated (n = 10) or conventional (n = 9) HTO. In order to achieve a sufficient amount of correction in all legs the weight-bearing line was aimed at 80 percent of the width of the tibial plateau.The mean deviation of the weight-bearing line from the desired 80 percent was 1 percent in the navigated and 8.6 percent in the conventional operated legs (p = 0.002). The weight-bearing line of all navigated but only 5 of the 9 conventional operated legs was within a ± 5 percent tolerance level (p = 0.33).Navigated open-wedge HTO achieved better correction of the weight-bearing line than the conventional method in human cadaver legs. Future studies have to prove this advantage in a clinical setting and it''s effect on patient outcome.     

Analysis of the histologic features in the differential diagnosis of intrahepatic neonatal cholestasis

AIM： To compare the histologic features of the liver in intrahepatic neonatal cholestasis （IHNC） with infectious, genetic-endocrine-metabolic, and idiopathic etiologies. METHODS： Liver biopsies from 86 infants with IHNC were evaluated. The inclusion criteria consisted of jaundice beginning at 3 mo of age and a hepatic biop- sy during the 1st year of life. The following histologic features were evaluated： cholestasis, eosinophilia, giant cells, erythropoiesis, siderosis, portal fibrosis, and the presence of a septum. RESULTS： Based on the diagnosis, patients were classified into three groups： group 1 （infectious; n = 18）, group 2 （genetic-endocrine-metabolic; n = 18）, and group 3 （idiopathic; n = 50）. There were no significant differences with respect to the following variables： cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and presence of a septum. A significant dif- ference was observed with respect to erythropoiesis, which was more severe in group 1 （Fisher＇s exact test, P = 0.016）. CONCLUSION： A significant difference was observed in IHNC of infectious etiology, in which erythropoiesis was more severe than that in genetic-endocrine-meta- bolic and idiopathic etiologies, whereas there were no significant differences among cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and the presence of a septum.     

Intubation for patients with overdose: Time to move on from the Glasgow Coma Scale

Patients frequently present to the ED with drug overdose and reduced conscious level leading to coma. There is considerable practice variation around which patients require intubation. Indications include: (i) respiratory failure (including airway obstruction); (ii) to facilitate specific therapies or intubation as a therapy in itself; and (iii) for airway protection in the unprotected airway. We argue that intubating a patient purely for (iii) is outdated and that most patients can be safely observed. There is a paucity of good quality research in the area of drug overdose with reduced consciousness. Teaching may be outdated and based on the use of the Glasgow Coma Scale in head trauma. Current low quality research suggests observation is safe. We recommend that patients undergo an individualised risk assessment of the need for intubation. We propose a flow diagram to aid clinicians in safely observing comatose overdose patients. This can be applied if the drug is unknown, or there are multiple drugs involved.     

Advanced cutaneous squamous cell carcinoma of the head in two renal transplanted patients treated with cemiplimab

It is well known that organ transplant recipients are prone to develop non-melanoma skin cancers, particularly cutaneous squamous cell carcinoma (cSCC). This is explained by the long-term use of immunosuppressants and thus the decrease of the immunosurveillance that protects from developing malignant tumours. Solid organ transplant recipients (SOTRs) are 65–250 times more likely to develop cSCC compared to the general population (Am J Transplant 2017; 17: 2509). Moreover, in these patients cSCCs follow a more aggressive course. Close follow-up and regular skin check-ups by a dermatologist are, therefore, crucial in the management of these patients. When detected early, cSCC can be easily and effectively treated by a simple excision. However, when advanced, outcomes are poor. Immune checkpoints inhibitors (ICIs) have been recently added to our arsenal and represent a breakthrough, having proved to be effective in achieving long-term responses. We, hereby, present two cases of difficult-to-treat cSCCs in renal transplanted patients.