54 research outputs found
Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire
Idiosyncratic adverse drug reactions are unpredictable, dose independent and
potentially life threatening; this makes them a major factor contributing to
the cost and uncertainty of drug development. Clinical data suggest that many
such reactions involve immune mechanisms, and genetic association studies have
identified strong linkage between drug hypersensitivity reactions to several
drugs and specific HLA alleles. One of the strongest such genetic associations
found has been for the antiviral drug abacavir, which causes severe adverse
reactions exclusively in patients expressing the HLA molecular variant B*57:01.
Abacavir adverse reactions were recently shown to be driven by drug-specific
activation of cytokine-producing, cytotoxic CD8+ T cells that required
HLA-B*57:01 molecules for their function. However, the mechanism by which
abacavir induces this pathologic T cell response remains unclear. Here we show
that abacavir can bind within the F-pocket of the peptide-binding groove of
HLA-B*57:01 thereby altering its specificity. This supports a novel explanation
for HLA-linked idiosyncratic adverse drug reactions; namely that drugs can
alter the repertoire of self-peptides presented to T cells thus causing the
equivalent of an alloreactive T cell response. Indeed, we identified specific
self-peptides that are presented only in the presence of abacavir, and that
were recognized by T cells of hypersensitive patients. The assays we have
established can be applied to test additional compounds with suspected HLA
linked hypersensitivities in vitro. Where successful, these assays could speed
up the discovery and mechanistic understanding of HLA linked hypersensitivities
as well as guide the development of safer drugs
Measuring the predictability of life outcomes with a scientific mass collaboration.
How predictable are life trajectories? We investigated this question with a scientific mass collaboration using the common task method; 160 teams built predictive models for six life outcomes using data from the Fragile Families and Child Wellbeing Study, a high-quality birth cohort study. Despite using a rich dataset and applying machine-learning methods optimized for prediction, the best predictions were not very accurate and were only slightly better than those from a simple benchmark model. Within each outcome, prediction error was strongly associated with the family being predicted and weakly associated with the technique used to generate the prediction. Overall, these results suggest practical limits to the predictability of life outcomes in some settings and illustrate the value of mass collaborations in the social sciences
Diagnosis and treatment of Chronic Constipation and Obstructed Defecation (part II: treatment)
The second part of the Consensus Statement of the
Italian Association of Hospital Gastroenterologists
and Italian Society of Colo-Rectal Surgery reports on
the treatment of chronic constipation and obstructed
defecation. There is no evidence that increasing fluid
intake and physical activity can relieve the symptoms
of chronic constipation. Patients with normal-transit
constipation should increase their fibre intake through
their diet or with commercial fibre. Osmotic laxatives
may be effective in patients who do not respond to
fibre supplements. Stimulant laxatives should be reserved
for patients who do not respond to osmotic
laxatives. Controlled trials have shown that serotoninergic
enterokinetic agents, such as prucalopride, and
prosecretory agents, such as lubiprostone, are effective
in the treatment of patients with chronic constipation.
Surgery is sometimes necessary. Total colectomy
with ileorectostomy may be considered in patients
with slow-transit constipation and inertia coli who are
resistant to medical therapy and who do not have
defecatory disorders, generalised motility disorders or
psychological disorders. Randomised controlled trials
have established the efficacy of rehabilitative treatment
in dys-synergic defecation. Many surgical procedures
may be used to treat obstructed defecation in
patients with acquired anatomical defects, but none is
considered to be the gold standard. Surgery should be
reserved for selected patients with an impaired quality
of life. Obstructed defecation is often associated with
pelvic organ prolapse. Surgery with the placement of
prostheses is replacing fascial surgery in the treatment
of pelvic organ prolapse, but the efficacy and safety of
such procedures have not yet been established
Diagnosis and treatment of Chronic Constipation and Obstructed Defecation (part II: treatment)
The second part of the Consensus Statement of the
Italian Association of Hospital Gastroenterologists
and Italian Society of Colo-Rectal Surgery reports on
the treatment of chronic constipation and obstructed
defecation. There is no evidence that increasing fluid
intake and physical activity can relieve the symptoms
of chronic constipation. Patients with normal-transit
constipation should increase their fibre intake through
their diet or with commercial fibre. Osmotic laxatives
may be effective in patients who do not respond to
fibre supplements. Stimulant laxatives should be reserved
for patients who do not respond to osmotic
laxatives. Controlled trials have shown that serotoninergic
enterokinetic agents, such as prucalopride, and
prosecretory agents, such as lubiprostone, are effective
in the treatment of patients with chronic constipation.
Surgery is sometimes necessary. Total colectomy
with ileorectostomy may be considered in patients
with slow-transit constipation and inertia coli who are
resistant to medical therapy and who do not have
defecatory disorders, generalised motility disorders or
psychological disorders. Randomised controlled trials
have established the efficacy of rehabilitative treatment
in dys-synergic defecation. Many surgical procedures
may be used to treat obstructed defecation in
patients with acquired anatomical defects, but none is
considered to be the gold standard. Surgery should be
reserved for selected patients with an impaired quality
of life. Obstructed defecation is often associated with
pelvic organ prolapse. Surgery with the placement of
prostheses is replacing fascial surgery in the treatment
of pelvic organ prolapse, but the efficacy and safety of
such procedures have not yet been established
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