Identifying women who might benefit from higher doses of folic acid in pregnancy

Question One of my epileptic patients who takes carbamazepine is planning to become pregnant. She told me that Motherisk advised her to take 5 mg of folic acid daily until the end of the first trimester. Are there other women who need more than the regular dose of folic acid included in prenatal vitamins?Answer Women who are at high risk of having babies with neural tube defects and who would benefit from higher doses of folic acid include those with certain folate-enzyme genotypes, previous pregnancies with neural tube defects, diabetes, malabsorption disorders, or obesity, or those who take antifolate medications or smoke. Such women should take 5 mg/d of folic acid for the 2 months before conception and during the first trimester.     

MitraClip for Papillary Muscle Rupture in Patient With Cardiogenic Shock

We report the successful use of the MitraClip device (Abbott Vascular, Santa Clara, CA) in a 68-year-old man with posterolateral ST-elevation myocardial infarction complicated by papillary muscle rupture and cardiogenic shock.     

The Defect in the Hurler and Scheie Syndromes: Deficiency of α-L-Iduronidase

Skin fibroblasts cultured from patients affected with the Hurler or Scheie syndromes (mucopoly-saccharidoses I or V, respectively) have a functional deficiency of a protein required for catabolism of sulfated mucopolysaccharide that has been designated the "Hurler corrective factor." We now show Hurler factor purified from normal human urine to be associated with alpha-L-iduronidase activity. Cell lines deficient in Hurler corrective factor have no detectable activity of alpha-L-iduronidase (less than 3% of that found in cells from individuals of other genotypes). Such correspondence indicates that Hurler corrective factor and alpha-L-iduronidase are the same entity. Correction of deficient cells is accompanied by an efficient uptake of alpha-L-iduronidase from the medium.     

Effect of different swallow time intervals on the nutcracker esophagus

OBJECTIVE: Nutcracker esophagus (NE) is defined as the presence of peristaltic contractions in which the average distal esophageal amplitude is greater than 180 mm Hg. The underlying mechanism responsible for these abnormalities is not known. The aim of this study was to test the hypothesis that NE might be caused by a defect in the inhibitory pathway controlling esophageal peristalsis. METHODS: Eight patients with NE (seven women, 1 man, mean age 50 yr) and eight age- and sex-matched normal volunteers (seven women, 1 man, mean age 48 yr) underwent a special protocol using three-channel (3, 8, and 16 cm above the lower esophageal sphincter) solid state esophageal manometry to evaluate deglutitive inhibition. Ten pairs of 5 ml of wet swallows were given at each of five different time intervals (30, 20, 15, 10, and 5 s). Pairs of swallows were spaced by 30 s, and different time intervals were spaced by 1 min. Tracings were recorded using a computer program and blindly automatically analyzed for both amplitude and duration of the contraction separately for the first and second swallow of each pair. Presence of deglutitive inhibition or muscle refractoriness was assessed according to interactions between the first and second swallow of the pair. Results were found abnormal when larger than the mean percent variation of the second and first swallow calculated for the 30-s interval, considered as baseline for each participant. Statistics included paired and nonpaired nonparametrical comparisons as appropriate. RESULTS: The median amplitude for the NE was 202 mm Hg (range 186-376) and for the controls was 118 mm Hg (range 64-167) (p = 0.0002). The median duration in the NE group was 5.1 s (range 4-9.3) versus 4.1 (range 3.3-5.0) for the controls (p = 0.02). The percent variation in duration (p = 0.31), amplitude (p = 0.42), and propagation velocity of the peristaltic waves (p = 0.69) did not differ between the control and NE groups. Peristalsis frequency dropped at the 5-s interval for both studied groups (p = 0.84). CONCLUSION: Central and local inhibitory mechanisms induced by closely timed swallows are preserved in the NE and do not explain the mechanism of the high amplitude and long duration contractions.     

Reply to ‘Indication bias or protopathic bias?’

Aim

The aim of the study was to characterize the extent of indication bias resulting from the excessive use of NSAIDs on the days preceding a spontaneous abortion to relieve pain.

Methods

We used data from a retrospective cohort study assessing the risk for spontaneous abortions following exposure to NSAIDs. Three definitions of exposure for cases of spontaneous abortions were compared, from the first day of pregnancy until the day of spontaneous abortion and until 3 and 2 days before a spontaneous abortion. Statistical analysis was performed using multivariate time programmed Cox regression.

Results

A sharp increase was observed in the dispensation of indomethacin, diclofenac and naproxen, and a milder increase was found in the use of ibuprofen during the week before a spontaneous abortion. Non- selective COX inhibitors in general and specifically diclofenac and indomethacin were found to be associated with spontaneous abortions when the exposure period was defined until the day of spontaneous abortion (hazard ratio (HR) 1.15, 95% confidence interval (CI) 1.04, 1.28; HR 1.31, 95% CI 1.08, 1.59 and HR 3.33, 95% CI 2.09, 5.29, respectively). The effect disappears by excluding exposures occurring on the day before the spontaneous abortion for non-selective COX inhibitors and on the last week before the spontaneous abortion for indomethacin. In general, decreasing HRs were found with the exclusion of exposures occurring on the days immediately before the spontaneous abortion.

Conclusions

The increased use of NSAIDs during the last few days that preceded a spontaneous abortion to relieve pain associated with the miscarriage could bias studies assessing the association between exposure to NSAIDs and spontaneous abortions.     

De novo design of β-helical polypeptides

Many proteins, including several growth factor receptors such as the IGF-1R and EGFR family, contain variants of the β-helix fold. Inspection of the irregular protein β-helices suggested that different families of regular β-helical polypeptides can be designed using a series of hinged vectors and the constraints imposed by the geometry of a peptide backbone. We have conceived β-helices with five and six β-strands per turn and designed, in detail, a series of regular β-helices with rhomboidal or triangular cross-sections. Each β-helix was modeled by threading C^α atoms to follow the vectorial β-helix and then creating the H-bonded polypeptide backbone and appropriate side-chain orientations. The conformational stability of these regular β-helices was assessed using molecular dynamics simulations. Several potential repeat amino acid sequences were identified for different geometries of β-helix. Regular β-helices offer new possibilities for the study of protein folding, the production of nanofibers, catalysts, inhibitors of growth factor receptors and drug carriers.     

Antigen presentation,autoantibody production,and therapeutic targets in autoimmune liver disease

The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.