Two recent articles in Science Translational
Medicine have opened new avenues in the prevention and treatment of
lethal dengue disease. Researchers from the Australia have unraveled
much of the mystery of lethal dengue disease. In 2000, their group had
developed a way to test for dengue by measuring concentrations of the
NS1 protein in the bloodstream. They then chanced across a study from
Thailand which found that patients with higher NS1 levels went on to
have more severe disease. So they started wondering whether NS1 actually
had a direct effect besides being just an infection marker. They found
that the NS1 protein activated mouse macrophages and human peripheral
blood lymphocytes via toll-like receptor 4 (TLR4) resulting in a massive
release of inflammatory cytokines. What they then demonstrated is
breathtakingly important. They demonstrated that this uncontrolled
inflammatory response could be blocked by using TLR4 antagonists and
antibodies against TLR.
The second set of researchers from University of
California found that when mice were injected with NS1, they threw up an
inflammatory response with endothelial leakage; and when they were
injected with both NS1 and a sublethal dose of dengue virus 2 it
resulted in a lethal inflammatory storm. But if the mice were immunized
previously with NS1 or if they were given monoclonal antibodies against
NS1, they were protected against lethal dengue disease.
These landmark studies have shown that NS1 protein
will be an important constituent for any vaccine against dengue and
drugs that target NS1 or TLR4 might be potentially effective against
lethal dengue disease. (Science Translational Medicine 9 September
2015)
Bedaquilone for Tuberculosis
Bedaquilone belongs to a new class of drugs called
the dairiquinolones, and acts by inhibiting the mycobacterial ATP
synthetase. It received fast track approval by the Food and Drug
Administration (FDA) at the end of 2012 for the treatment of adults with
multidrug-resistant pulmonary tuberculosis. It is being touted as the
second major advance in the field of tuberculosis after Expert MTB/Rif
test was developed in 2010.
The Director General of Health (India) announced that
it will become available in India within the next three months. It
recently underwent clinical trials at national level for safety and
efficacy. Four nodal cities – Mumbai, Chennai, Bangalore and Kolkata –
will control its distribution to required districts. Its distribution
will be strictly regulated. The dose in adults is 400 mg daily for two
weeks followed by 200 mg thrice a week for a maximum of 22 weeks.
Adverse effects are mainly cardiac and hepatic. (The Indian Express
11 September 2015)
Neonates With Diabetes who Require no Insulin
In the 1970’s, the entity of maturity onset diabetes
of the young (MODY) was first described. This was a peculiar kind of
diabetes distinct from both Type I and Type II. These were young people
who developed diabetes but did not require insulin, did not go into
ketosis, and often responded to oral suphonylureas. Some never developed
the complications of hyperglycemia and never required any drugs. In the
1990’s, it was confirmed that mutations encoding for the glucokinase
gene HNF1A and HNF4 A were responsible for these manifestations in some
of the people. Though MODY accounts for just 1-2% of diabetes, we need
to know when to suspect it. Neonatal diabetes (onset <6 mo of age),
strong family history of diabetes, type 1 diabetes who need less than
0.5 units/kg/day of insulin, persistently detectable C-peptide and
negative antibody status are good clues. In type 2 diabetes those who
are non obese or lacking markers for metabolic syndrome also need to be
worked up for MODY.
A recent multicentric study evaluated all the genes associated with
neonatal diabetes (diabetes with onset <6 mo) using comprehensive
next-generation sequencing. Causal mutations have been identified in 82%
of patients. Patients with mutations in the glucokinase gene did not
need any treatment and identification of a potassium channel mutation
indicated that patient will respond to oral sulphonylureas. (The
Lancet 2015;386:934-5).