Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dop

Ambient temperature and kidney function in primary care patients

Introduction Exposure to high ambient temperatures is associated with a risk of acute kidney injury. However, evidence comes from emergency departments or extreme weather exposures. It is unclear whether temperature-related adverse kidney outcomes can also be detected at a community level in a temperate climate zone. Methods In a 9.5-year retrospective cohort study we correlated estimated glomerular filtration rate (eGFR) values of Swiss adult primary care patients from the FIRE cohort (Family medicine Research using Electronic medical records) with same-day maximum local ambient temperature data. We investigated 5 temperature groups (< 15 °C, 15–19 °C, 20–24 °C, 25–29 °C and  ≥ 30 °C) as well as possible interactions for patients with increased kidney vulnerability (chronic heart failure, diabetes, chronic kidney disease, therapy with renin–angiotensin–aldosterone-system (RAAS) inhibitors, diuretics or non-steroidal anti-inflammatory drugs). Results We included 18,000 primary care patients who altogether provided 132,176 creatinine measurements. In the unadjusted analysis, higher ambient temperatures were associated with lower eGFR across all age and vulnerability groups. In the adjusted models, we did not find a consistent association.The highest ambient temperature differences (> 25 or > 30 versus < 15 °C) were associated with marginally reduced kidney function only in patients with ≥ 3 risk factors for kidney vulnerability, with a maximum estimated glomerular filtration rate reduction of −2.9 ml/min/1.73m$^{2}$ (SE 1.0), P 0.003. Discussion In a large primary care cohort from a temperate climate zone, we did not find an association between ambient temperatures and kidney function. A marginal inverse association in highly vulnerable patients is of unclear clinical relevance

Mechanistic basis of choline import involved in teichoic acids and lipopolysaccharide modification

Phosphocholine molecules decorating bacterial cell wall teichoic acids and outer-membrane lipopolysaccharide have fundamental roles in adhesion to host cells, immune evasion, and persistence. Bacteria carrying the operon that performs phosphocholine decoration synthesize phosphocholine after uptake of the choline precursor by LicB, a conserved transporter among divergent species.; Streptococcus pneumoniae; is a prominent pathogen where phosphocholine decoration plays a fundamental role in virulence. Here, we present cryo-electron microscopy and crystal structures of; S. pneumoniae; LicB, revealing distinct conformational states and describing architectural and mechanistic elements essential to choline import. Together with in vitro and in vivo functional characterization, we found that LicB displays proton-coupled import activity and promiscuous selectivity involved in adaptation to choline deprivation conditions, and describe LicB inhibition by synthetic nanobodies (sybodies). Our results provide previously unknown insights into the molecular mechanism of a key transporter involved in bacterial pathogenesis and establish a basis for inhibition of the phosphocholine modification pathway across bacterial phyla

Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells through Atorvastatin

Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, exhibit numerous functions related to inflammation, such as MHC class II down-regulation, interference with T cell adhesion, and induction of apoptosis. Here we demonstrate that both subcutaneous and oral administration of atorvastatin inhibit the development of actively induced chronic experimental autoimmune encephalomyelitis in SJL/J mice and significantly reduce the inflammatory infiltration into the central nervous system (CNS). When treatment was started after disease onset, atorvastatin reduced the incidence of relapses and protected from the development of further disability. Both the reduced autoreactive T cell response measured by proliferation toward the encephalitogenic peptide PLP139–151 and the cytokine profile indicate a potent blockade of T helper cell type 1 immune response. In in vitro assays atorvastatin not only inhibited antigen-specific responses, but also decreased T cell proliferation mediated by direct TCR engagement independently of MHC class II and LFA-1. Inhibition of proliferation was not due to apoptosis induction, but linked to a negative regulation on cell cycle progression. However, early T cell activation was unaffected, as reflected by unaltered calcium fluxes. Thus, our results provide evidence for a beneficial role of statins in the treatment of autoimmune attack on the CNS