TASK DEFINITION: Given a passage with a context and an answer, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.
PROBLEM: Context: Assessment of the activity of thioridazine towards Mycobacterium tuberculosis (Mtb), invitro and invivo as a single drug and in combination with tuberculosis (TB) drugs.', 'The invitro activity of thioridazine as single drug or in combination with TB drugs was assessed in terms of MIC and by use of the time-kill kinetics assay. Various Mtb strains among which the Beijing genotype strain BE-1585 were included. Invivo, mice with TB induced by BE-1585 were treated with a TB drug regimen with thioridazine during 13 weeks. Therapeutic efficacy was assessed by the change in mycobacterial load in the lung, spleen and liver during treatment and 13 weeks post-treatment.', 'Invitro, thioridazine showed a concentration-dependent and time-dependent bactericidal activity towards both actively-replicating and slowly-replicating Mtb. Thioridazine at high concentrations could enhance the activity of isoniazid and rifampicin, and in case of isoniazid resulted in elimination of mycobacteria and prevention of isoniazid-resistant mutants. Thioridazine had no added value in combination with moxifloxacin or amikacin. In mice with TB, thioridazine was poorly tolerated, limiting the maximum tolerated dose (MTD). The addition of thioridazine at the MTD to an isoniazid-rifampicin-pyrazinamide regimen for 13 weeks did not result in enhanced therapeutic efficacy.
Answer: Thioridazine is bactericidal towards Mtb invitro, irrespective the mycobacterial growth rate and results in enhanced activity of the standard regimen. The invitro activity of thioridazine in potentiating isoniazid and rifampicin is not reflected by improved therapeutic efficacy in a murine TB-model.

SOLUTION: Is enhancement of in vitro activity of tuberculosis drugs by addition of thioridazine reflected by improved in vivo therapeutic efficacy?

PROBLEM: Context: Central core disease is a congenital myopathy, characterized by presence of central core-like areas in muscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is caused by mutations in the human ryanodine receptor gene (RYR1), which encodes a calcium-release channel. Since the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three 'hot spots', with particular attention to the C-terminal region. Recent next-generation sequencing methods are now identifying multiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult.", "In a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a new case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1 gene identified two different missense mutations: c.14256 A >C polymorphism in exon 98 and c.14693 T >C in exon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed because patient's daughter, mother and sister carried only the exon 98's mutation, a synonymous variant that was subsequently found in the frequency of 013-0,05 of alleles. Further next generation sequencing study of the whole RYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and 8 polymorphisms in heterozygosis.
Answer: Considering that patient's relatives showed no pathologic phenotype, and the phenotype presented by the patient is within the range observed in other central core disease patients with the same mutation, it was concluded that the c.14256 A >C polymorphism alone is not responsible for disease, and the associated additional silent polymorphisms are not acting as modifiers of the primary pathogenic mutation in the affected patient. The case described above illustrates the present reality where new methods for wide genome screening are becoming more accessible and able to identify a great variety of mutations and polymorphisms of unknown function in patients and their families.

SOLUTION: Do silent polymorphisms in the RYR1 gene modify the phenotype of the p.4898 I > T pathogenic mutation in central core disease : a case report?

PROBLEM: Context: Increased arterial stiffness has been found in patients with chronic high-grade inflammatory diseases. Whether mitigation of low-grade systemic inflammation, through a low-cholesterol/low-saturated fat diet, may have a role in improving arterial stiffness is still untested.', 'We investigated whether variations in blood lipids and plasma C-reactive protein induced by low-cholesterol/low-saturated fat diet are associated with variations in large-artery stiffness in hypercholesterolaemia.', 'Thirty-five patients with primary hypercholesterolaemia and 15 normal control subjects were recruited for the study. Hypercholesterolaemic patients followed an 8-week low-cholesterol/low-saturated fat diet (30% total fat, 5% saturated fat, cholesterol <200 mg/daily). Anthropometric characteristics, blood lipids, plasma C-reactive protein and arterial stiffness were measured at baseline and after the diet.', 'Arterial stiffness and C-reactive protein levels were higher in hypercholesterolaemic patients than in controls. Significant reductions in body weight (2 kg, 3%), plasma total cholesterol (13.4 mg/dl, 5.3%), low-density lipoprotein cholesterol (11.2 mg/dl, 6.4%), C-reactive protein (0.7 mg/l, 39%) and arterial stiffness (from 8.9+/-2.0 to 8.1+/-1.9 m/s, 11%) were achieved among hypercholesterolaemic patients after the 8-week diet (P<0.05 for all). Bivariate correlations and multivariate analysis showed reduction in arterial stiffness after short-term diet to be associated with reduction of plasma C-reactive protein levels (r=0.59, beta=0.38, P<0.05 for both).
Answer: Short-term low-cholesterol/low-saturated fat diet in hypercholesterolaemia may be effective in improving large artery stiffness, likely through the mitigation of low-grade systemic inflammation.

SOLUTION:
Is attenuation of inflammation with short-term dietary intervention associated with a reduction of arterial stiffness in subjects with hypercholesterolaemia?