Receptor activator of nuclear factor kappa B ligand (RANKL) and its natural antagonist, osteoprotegerin (OPG), are, respectively, an indispensable factor and a potent inhibitor for osteoclast ...differentiation, activity, and survival. The development of a human monoclonal antibody to RANKL, denosumab, constitutes a novel approach to prevent fragility fractures in osteoporosis, skeletal complications of malignancy, and potentially bone erosions in rheumatoid arthritis (RA). In addition to being expressed by osteoblasts, RANKL is abundantly produced by activated T cells, and synoviocytes in RA, whereas its receptor, RANK, is also expressed by monocytes/macrophages and dendritic cells. However, in preclinical and clinical studies of RA--including patients with some degree of immunosuppression--RANKL inhibitors did not significantly alter inflammatory processes. RANKL, RANK, and OPG deficiency in murine models highlights the important role of this pathway in the development and maturation of the immune system in rodents, including functions of T and/or B cells, whereas OPG overexpression in mice and rats seems innocuous with regard to immunity. In contrast, loss-of-function mutations in humans have more limited effects on immune cells. In clinical studies, the overall rate of infections, cancer, and death was similar with denosumab and placebo. Nevertheless, the risk of severe infections and cancer in some specific tissues remains to be carefully scrutinized.
Let
X
be a separable Hilbert space with norm
⋅
and let
T
> 0. Let
Q
be a linear, self-adjoint, positive, trace class operator on
X
, let
F
:
X
→
X
be a (smooth enough) function and let
W
(
t
) be a
X
...-valued cylindrical Wiener process. For
α
∈ 0, 1/2 we consider the operator
A
:
=
−
(
1
/
2
)
Q
2
α
−
1
:
Q
1
−
2
α
(
X
)
⊆
X
→
X
. We are interested in the mild solution
X
(
t
,
x
) of the semilinear stochastic partial differential equation
d
X
(
t
,
x
)
=
A
X
(
t
,
x
)
+
F
(
X
(
t
,
x
)
)
d
t
+
Q
α
d
W
(
t
)
,
t
∈
(
0
,
T
;
X
(
0
,
x
)
=
x
∈
X
,
and in its associated transition semigroup
P
(
t
)
φ
(
x
)
:
=
E
φ
(
X
(
t
,
x
)
)
,
φ
∈
B
b
(
X
)
,
t
∈
0
,
T
,
x
∈
X
;
where
B
b
(
X
)
is the space of the bounded and Borel measurable functions. We will show that under suitable hypotheses on
Q
and
F
,
P
(
t
) enjoys regularizing properties, along a continuously embedded subspace of
X
. More precisely there exists
K
:=
K
(
F
,
T
) > 0 such that for every
φ
∈
B
b
(
X
)
,
x
∈
X
,
t
∈ (0,
T
and
h
∈
Q
α
(
X
)
it holds
|
P
(
t
)
φ
(
x
+
h
)
−
P
(
t
)
φ
(
x
)
|
≤
K
t
−
1
/
2
∥
Q
−
α
h
∥
.
Summary
According to regulation (EC) 1,394/2007 on Advanced Therapy Medicinal Products (ATMPs), manipulation of corneal limbal stem cells for clinical applications aiming to treat limbal stem cell ...deficiency (LSCD) has to be carried out in certified Cell Factories according to the Good Manufacturing Practises (GMP). For hospitals and tissue banks wanting to provide ATMPs many challenges lie ahead, including (1) setting up GMP laboratories, (2) validating personnel, procedures and analytical methods continuously and (3) dealing with the costs associated with the maintenance of pharmaceutical grade environments. Results from clinical trials have been reported by different groups worldwide and data are so promising that the European Medicines Agency has recently issued the first marketing authorization for a corneal stem cell‐based ATMP. Despite this, the appropriate selection of the patients and follow‐up analyses remain crucial for successful treatments. In the meantime, R&D studies are looking further ahead with research focusing on cell therapy‐based strategies for the treatment of pathologies affecting the conjunctival epithelium and the corneal endothelium and on gene therapy approaches for rare disorders, such as the EEC syndrome.
Loss of body weight is associated with bone loss, and body weight gain is associated with increased bone formation. The molecular mechanisms linking body weight, body composition, and bone density ...are now better understood. Lean mass is likely to have a significant, local effect on bone modeling and remodeling through mechanotransduction pathways. In contrast to the local regulation of bone formation and resorption by muscle-derived stimuli, peripheral body fat appears to influence bone mass via secretion of systemic, endocrine factors that link body weight to bone density even in non-weight bearing regions (e.g., the forearm). The cytokine-like hormone leptin, which is secreted by fat cells, is an important candidate molecule linking changes in body composition with bone formation and bone resorption. Increases in body fat increase leptin levels and stimulate periosteal bone formation through its direct anabolic effects on osteoblasts, and through central (CNS) effects including the stimulation of the GH-IGF-1 axis and suppression of neuropeptide Y, a powerful inhibitor of bone formation. Stimulation of beta2-adrenergic receptors through central (hypothalamic) leptin receptors does, however, increase remodeling of trabecular bone, resulting in a lower cancellous bone volume that may be better adapted to a concomitantly larger cortical bone compartment. These findings suggest that body weight and body fat can regulate bone mass and structure through molecular pathways that are independent of load-bearing. Furthermore, pharmacological manipulation of the signaling pathways activated by leptin may have significant potential for the treatment and prevention of bone loss.
Summary
Discontinuation of denosumab (Dmab) therapy is associated with lower serum CTX levels in osteoporotic patients previously exposed to bisphosphonates compared to those who were not.
...Introduction
Discontinuation of Dmab therapy is followed by a transient increase of bone turnover markers (BTMs) above pretreatment values, together with accelerated bone loss, and potentially an increased risk of multiple vertebral fractures. Since a substantial proportion of patients discontinuing Dmab have previously been exposed to bisphosphonates (BPs), we hypothesized that previous BP therapy could attenuate this increase in bone turnover because of the prolonged biological effects of BPs on bone.
Methods
In a retrospective observation, we assessed serum CTX levels between 7 and 24 months after the last Dmab injection in 37 patients (33 women and 4 men, aged 50 to 84 years). CTX levels were analyzed according to the number of Dmab injections (1 or multiple) and previous exposure to BPs.
Results
In 8 patients who had received only 1 Dmab injection, 7 out of 8 were previously on BPs and none of them showed CTX values above the premenopausal range after Dmab discontinuation. CTX also remained in the premenopausal range in 14 out of 17 patients who discontinued Dmab after multiple (4.1 ± 1.4, range 2–7) injections but were previously exposed to BPs (mean exposure 6.9 ± 5.8 years, range 11 months–15 years; mean time interval between BP exposure and Dmab initiation 25 ± 10 months, range 0–48). In contrast, in 12 patients who discontinued Dmab after multiple (5, range 3–9) injections without prior exposure to BPs, mean CTX levels as measured on average 11.3 months (range 6–23) after the last Dmab injection were above the upper limit of premenopausal range (mean +114%, range 28–320%,
p
= 0.003–0.005 vs previous BPs).
Conclusion
The higher CTX levels occurring after Dmab discontinuation in patients who have received multiple injections may be prevented by prior exposure to BPs. This observation may be related to the persistent effects of BPs on bone that prevent the resorbing activity of newly formed osteoclasts when RANK Ligand is no more antagonized.
Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. Yet the ...identification and management of fracture risk in these patients remains challenging. This review explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (i.e., FRAX) in these patients. It further reviews the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population. We finally propose an algorithm for the identification and management of diabetic patients at increased fracture risk.
The recent pandemic due to SARS-CoV-2 has brought to light the need for strategies to mitigate contagion between human beings. Apart from hygiene measures and social distancing, air ventilation ...highly prevents airborne transmission within enclosed spaces. Among others, educational environments become critical in strategic planning to control the spread of pathogens and viruses amongst the population, mainly in cold conditions. In the event of a virus outbreak – such as COVID or influenza – many school classrooms still lack the means to guarantee secure and healthy environments.
The present review examines school contexts that implement air ventilation strategies to reduce the risk of contagion between students. The analysed articles present past experiences that use either natural or mechanical systems assessed through mathematical models, numerical models, or full-scale experiments. For naturally ventilated classrooms, the studies highlight the importance of the architectural design of educational spaces and propose strategies for aeration control such as CO2-based control and risk-infection control. When it comes to implementing mechanical ventilation in classrooms, different systems with different airflow patterns are assessed based on their ability to remove airborne pathogens considering parameters like the age of air and the generation of airflow streamlines. Moreover, studies report that programmed mechanical ventilation systems can reduce risk-infection during pandemic events.
In addition to providing a systematic picture of scientific studies in the field, the findings of this review can be a valuable reference for school administrators and policymakers to implement the best strategies in their classroom settings towards reducing infection risks.
PDF
