Bezlotoxumab for the prevention of Clostridium difficile recurrence

Introduction: Clostridium difficile infection is a major economic and clinical burden, due to its high frequency of recurrence. Currently recommended treatments are not efficient for prevention and may contribute to the risk of recurrent infection. In recent years, research has focused on strategies to lessen this risk. Bezlotoxumab is a monoclonal antibody that prevents recurrences of C. difficile infection through the antagonism of toxin B.

Areas covered: In this review, the authors discuss the burden of C. difficile infection and its recurrences, the mechanisms underlying the recurrences, and current C. difficile treatments. They subsequently analyze the strategic therapeutic rationale for bezlotoxumab use, as well as the supporting clinical evidence.

Expert opinion: Bezlotoxumab is an attractive solution for reducing the unacceptable level of recurrence that occurs with the currently recommended C. difficile treatments and other alternative therapies under consideration. Even though bezlotoxumab has not been tested in large-scale trials exclusively in cases of already established recurrent C.difficile infection (rCDI), it has an advantage over current treatments in that it does not interfere with the patient’s gut flora while directly neutralizing the key virulence factor. Although cost remains an important factor against its widespread use, simpler administration, fewer side-effects, and better social acceptability justify its consideration for treating rCDI.     

MDCT-Based Finite Element Analysis for the Prediction of Functional Spine Unit Strength—An In Vitro Study

(1) Objective: This study aimed to analyze the effect of ligaments on the strength of functional spine unit (FSU) assessed by finite element (FE) analysis of anatomical models developed from multi-detector computed tomography (MDCT) data. (2) Methods: MDCT scans for cadaveric specimens were acquired from 16 donors (7 males, mean age of 84.29 ± 6.06 years and 9 females, mean age of 81.00 ± 11.52 years). Two sets of FSU models (three vertebrae + two disks), one with and another without (w/o) ligaments, were generated. The vertebrae were segmented semi-automatically, intervertebral disks (IVD) were generated manually, and ligaments were modeled based on the anatomical location. FE-predicted failure loads of FSU models (with and w/o ligaments) were compared with the experimental failure loads obtained from the uniaxial biomechanical test of specimens. (3) Results: The mean and standard deviation of the experimental failure load of FSU specimens was 3513 ± 1029 N, whereas of FE-based failure loads were 2942 ± 943 N and 2537 ± 929 N for FSU models with ligaments and without ligament attachments, respectively. A good correlation (ρ = 0.79, and ρ = 0.75) was observed between the experimental and FE-based failure loads for the FSU model with and with ligaments, respectively. (4) Conclusions: The FE-based FSU model can be used to determine bone strength, and the ligaments seem to have an effect on the model accuracy for the failure load calculation; further studies are needed to understand the contribution of ligaments.     

Are There Sex Differences in Knee Cartilage Composition and Walking Mechanics in Healthy and Osteoarthritis Populations?

Background

Women are at a greater risk for knee osteoarthritis (OA), but reasons for this greater risk in women are not well understood. It may be possible that differences in cartilage composition and walking mechanics are related to greater OA risk in women.

Questions/purposes

(1) Do women have higher knee cartilage and meniscus T_1ρ than men in young healthy, middle-aged non-OA and OA populations? (2) Do women exhibit greater static and dynamic (during walking) knee loading than men in young healthy, middle-aged non-OA and OA populations?

Methods

Data were collected from three cohorts: (1) young active (< 35 years) (20 men, 13 women); (2) middle-aged (≥ 35 years) without OA (Kellgren-Lawrence [KL] grade < 2) (43 men, 65 women); and (3) middle-aged with OA (KL > 1) (18 men, 25 women). T_1ρ and T₂ relaxation times for cartilage in the medial knee, lateral knee, and patellofemoral compartments and medial and lateral menisci were quantified with 3.0-T MRI. A subset of the participants underwent three-dimensional motion capture during walking for calculation of peak knee flexion and adduction moments, flexion and adduction impulses, and peak adduction angle. Differences in MR, radiograph, and gait parameters between men and women were compared in the three groups separately using multivariate analysis of variance.

Results

Women had higher lateral articular cartilage T_1ρ (men = 40.5 [95% confidence interval {CI}, 38.8–42.3] ms; women = 43.3 [95% CI, 41.9–44.7] ms; p = 0.017) and patellofemoral T_1ρ (men = 44.4 [95% CI, 42.6–46.3] ms; women = 48.4 [95% CI, 46.9–50.0] ms; p = 0.002) in the OA group; and higher lateral meniscus T_1ρ in the young group (men = 15.3 [95% CI, 14.7–16.0] ms; women = 16.4 [95% CI, 15.6–17.2] ms; p = 0.045). The peak adduction moment in the second half of stance was lower in women in the middle-aged (men = 2.05 [95% CI, 1.76–2.34] %BW*Ht; women = 1.66 [95% CI, 1.44–1.89] %BW*Ht; p = 0.037) and OA (men = 2.34 [95% CI, 1.76–2.91] %BW*Ht; women = 1.42 [95% CI, 0.89–1.94] %BW*Ht; p = 0.022) groups. Static varus from radiographs was lower in women in the middle-aged (men = 178° [95% CI, 177°–179°]; women = 180° [95% CI, 179°–181°]; p = 0.002) and OA (men = 176° [95% CI, 175°–178°]; women = 180° [95% CI, 179°–181°]; p < 0.001) groups. Women had lower varus during walking in all three groups (young: men = 4° [95% CI, 3°–6°]; women = 2° [95% CI, 0°–3°]; p = 0.013; middle-aged: men = 2° [95% CI, 1°–3°]; women = 0° [95% CI, −1° to 1°]; p = 0.015; OA: men = 4° [95% CI, 2°–6°]; women = 0° [95% CI, −2° to 2°]; p = 0.011). Women had a higher knee flexion moment (men = 4.24 [95% CI, 3.58–4.91] %BW*Ht; women 5.40 [95% CI, 4.58–6.21] %BW*Ht; p = 0.032) in the young group.

Conclusions

These data demonstrate differences in cartilage composition and gait mechanics between men and women in young healthy, middle-aged healthy, and OA cohorts. Considering the cross-sectional nature of the study, longitudinal research is needed to investigate if these differences in cartilage composition and walking mechanics are associated with a greater risk of lateral tibiofemoral or patellofemoral OA in women. Future studies should also investigate the relative risk of lateral versus medial patellofemoral cartilage degeneration risk in women compared with men.

Level of Evidence

Level III, retrospective study.     

I L- 15 trans-presentation regulates homeostasis of CD4^＋ T lymphocytes

Interleukin-15 （IL-15） is essential for the survival of memory CD8^＋ and CD4^＋ T cell subsets, and natural killer and natural killer T cells. Here, we describe a hitherto unreported role of IL-15 in regulating homoeostasis of naive CD4^＋ T cells. Adoptive transfer of splenocytes from non-obese diabetic （NOD） mice results in increased homeostatic expansion of T cells in lymphopenic NOD.scid.II15^-/- mice when compared to NOD.scid recipients. The increased accumulation of CD4^＋ T cells is also observed in NOD.II15^-/- mice, indicating that IL-15-dependent regulation also occurs in the absence of lymphopenia. NOD.scid mice lacking the I L- 15Ra chain, but not those lacking the common gamma chain, also show increased accumulation of CD4^＋ T cells. These findings indicate that the IL-15-mediated regulation occurs directly on CD4^＋ T cells and requires trans-presentation of IL-15. CD4^＋ T cells expanding in the absence of IL-15 signaling do not acquire the characteristics of classical regulatory T cells. Rather, CD4^＋ T cells expanding in the absence of IL-15 show impaired antigen-induced activation and IFN-7 production. Based on these findings, we propose that the IL-15-dependent regulation of the naive CD4^＋ T-cell compartment may represent an additional layer of control to thwart potentially autoreactive cells that escape central tolerance, while permitting the expansion of memory T cells.     

Antigen-nonspecific activation of CD8+ T lymphocytes by cytokines: relevance to immunity, autoimmunity, and cancer

Development of T lymphocytes and their survival in the periphery are dependent on signals emanating from cytokine receptors as well as the T cell antigen receptor (TCR). These two signaling pathways play distinct and complementary roles at various stages of T cell development, maturation, survival, activation and differentiation. During immune response to foreign antigens initiated by TCR signaling, cytokines play a key role in the expansion of activated T cells. Even though the initial activation of T cells occurs via the TCR, this requirement can be overcome under certain circumstances. During lymphopenia, cytokines trigger memory CD8⁺ T cells to undergo antigen non-specific homeostatic expansion, whereas naïve CD8⁺ T cells require both cytokines and TCR signaling. Recent reports show certain combinations of cytokines can induce proliferation and effector functions of naïve CD8⁺ T cells without concomitant stimulation via the TCR. While such antigen non-specific stimulation of naïve T cells might significantly boost the adaptive immune response, it could also have an undesirable effect of triggering potentially autoreactive cells. Understanding the mechanisms and the regulation of cytokine-driven stimulation of naïve CD8⁺ T cells may lead to novel strategies of intervention for autoimmune diseases. On the other hand, in vitro expansion of naïve CD8⁺ T cells by certain combinations of cytokines could be used to generate tumor-specific cells with ideal properties for cellular immunotherapy of cancer.     

Formulation of transdermal drug delivery system: matrix type, and selection of polymer- their evaluation

Goatskin is used instead of rat-skin to study the permeation and the results are compared. The percentage of permeation is double in goatskin. We have five different oils to study, how they influence permeation and all of them have improved permeation when used on goatskin. To analyze further two parameters-percentage and rate of permeation are used. When these five oils are used with salicyclic acid on goatskin the following results are obtained. The percentage of permeation is as follows [Caraway oil (48%) > Lemon oil (36%) > Peppermint oil (29%) > Lemon Grass oil (22%) > Citronella oil (19%)]. The caraway oil has the highest percentage of permeation whereas citronella oil has the lowest percentage of permeation. Caraway oil has three times more permeation than that of citronella oil. The selection of polymer for the formulation of TDDS was done basing on a comparative study of five polymers and their various combinations using such parameters as uniformity of weight, thickness and content and percentage and rate of diffusion counted. Results show that methylcellulose and hydroxy propyl methyl cellulose record more control release of salicyclic acid than the other polymers. Except HPMC all other polymers follow zero order kinematics. Basing on this experimental evidence transdermal patch of salicyclic acid was formed with HPMC, MC polymer incombination with caraway oil has permeating enhancer and evaluated using goatskin. Comparative study shows that there is two fold increases in the percentage of permeation.     

Combating blood stream infections during induction chemotherapy in children with acute myeloid leukemia: Single center results in India

Optimal management of infectious complication is the biggest challenge in children receiving chemotherapy for acute myeloid leukemia (AML). We have analyzed the data of children undergoing AML induction chemotherapy at our center from 2002 to 2016 and found that Gram‐negative infections are more predominant when compared to the published literature. There also has been a surge in multidrug‐resistant (MDR) infections over the last 4 years, which has increased the need for supportive care and escalated the cost of care. We have introduced certain novel methods to combat MDR sepsis and decrease mortality rates.