Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that NaV1.7C1143F exhibits partial loss-of-function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of NaV1.7, we found an excess of rare variants in a case-control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, although this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. Although the involvement of the SCN1A and SCN2A genes encoding NaV1.1 and NaV1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss-of-function of NaV1.7 channels in the etiology of rare familial ASD.

Assessment at one school of students' abilities and confidence in diabetic patients' education.

PURPOSE: To determine medical students' experiences in working with diabetic patients, their cognitive competence and their confidence in meeting diabetic patients' educational needs, and changes in their expertise with advancing education. METHOD: The study was conducted in March 1994 at the University of Illinois College of Medicine, where students work with ambulatory patients in a longitudinal primary care experience from their second year through graduation. A combined questionnaire and objective quiz was developed and distributed to 138 second-, third-, and fourth-year students. The students were asked whether they had had experience in seeing a newly diagnosed diabetic patient, in what setting, and whether they felt confident in educating such patients on various common topics. They were also asked about their interests in and preferences for learning about diabetic patients' education. A 50-item objective quiz on the management of diabetes followed the questionnaire. Data were analyzed with several statistical methods. RESULTS: In all, 65 of the students (47%) responded; the majority were third- or fourth-year students. The percentages of students who felt confident ranged from 83% who felt confident about counseling about exercise to only 16% who felt confident about pre-conception counseling. All of the students but one felt that diabetic patients' education was an important topic, and all but two were interested in it. The students' quiz scores showed no significant difference by year of training; for all the students the average score was 39.6% correct, with no increase in score for increased training. Also, the students who were more confident about their abilities to provide patient education on a certain topic were no more likely to have accurate information about that topic than were those who were not confident. CONCLUSION: Although they were clearly interested in diabetic patients' education, the students did not feel confident in providing it, nor did they have the cognitive competence to do so. Medical schools have a responsibility to students and to their patients to formally address the issues of patient education.

Beliefs and attitudes of persons with diabetes.

BACKGROUND AND OBJECTIVES: Physicians seem to agree that noncompliance by diabetic patients is a problem. Despite this, there have been few qualitative studies on the actual behaviors, beliefs, and attitudes of diabetic patients. The present study was conducted to explore these parameters to help discover ways that physicians might enhance diabetic patients' compliance. METHODS: This research used a variation of grounded qualitative theory to assess the beliefs and attitudes of 14 non-insulin, adult-onset diabetic patients with a disease duration of at least 3 years. Of these, seven were considered compliant and seven noncompliant by their primary physician. RESULTS: Most of the patients felt they had a good understanding of diabetes, were compliant with their medical regimen, and considered diabetes a serious disease. Although many of the patients expressed strong emotions of frustration and anger, a majority felt that diabetes had led them to a healthier and/or happier lifestyle. Noncompliant patients were more likely to believe that diabetes would not affect the eventual outcome of their lives. They were less likely to want no further information from their physician and less likely to report following their physician's instructions. CONCLUSIONS: A better understanding of patients' beliefs and attitudes may help physicians increase motivation, understanding, and compliance of diabetic patients.

Development of thyroid follicular adenoma on simvastatin therapy.

HMG-CoA reductase inhibitors (lovastatin, simvastatin, fluvastatin, pravastatin) constitute a potent class of cholesterol-lowering agents, which are increasingly being used these days for primary and secondary prevention of atherosclerotic heart disease. Despite having good overall safety and efficacy profiles, these medications can still cause significant adverse effects including transient elevation of hepatic transaminases, myopathy, and rhabdomyolysis. Preclinical studies have demonstrated a potential of neoplasia in rats. However in clinical trials HMG-CoA reductase inhibitors have not been found to be neoplastic in humans. The dosage used in humans is also significantly lower and therefore it is expected to have a good safety margin. But this may not be entirely true considering the mechanism of neoplastic transformation, which is thought to be different in humans as compared to other species. We report a patient, who developed follicular adenoma with prominent Hurthle cell changes after being on simvastatin for three months but not during one year of pravastatin therapy. In elderly female patients with hyperlipidemia requiring pharmacologic treatment, especially those with a prior history of multinodular goiter, one should consider using an agent which has not been shown to cause thyroid tumors even in animal models. Patients should continue to be followed with frequent periodic thyroid palpation in addition to the usual biochemical monitoring required while on these agents.

A new era for hospital liability.

Hospitals are no longer merely facilities with equipment where autonomous physicians practice; they owe a direct duty of reasonable care to patients. This dramatic transition for hospitals will ensure a sea of change in the character of hospital medical practice and management.

Laser chemically induced dynamic nuclear polarization study of the reaction between photoexcited flavins and tryptophan derivatives at 360 MHz.

Chemically induced dynamic nuclear polarization (CIDNP) is generated when tryptophan (Trp), its derivatives, or Trp-containing peptides react with photoexcited flavins in a 360-MHz NMR spectrometer. In contrast to tyrosine (Tyr), we find that the nuclear polarization of Trp originates in an electron-transfer reaction. By use of a series of Trp derivatives, the unpaired spin-density distribution of the Trp radical cation and the ground-state NMR spectrum of Trp are analyzed in detail. The signs and the relative magnitudes of the proton isotropic hyperfine coupling constants for each position around the indole ring in the radical cation deduced from these measurements are the following: position 3 greater than 2 approximately 4 approximately 6 greater than 1 greater than 5 greater than 7, with positions 1, 2, 3, 4, and 6 positive, 5 negative, and 7 essentially zero. This result is inconsistent with most available calculations of the unpaired spin-density distribution but is compatible with the pattern of electrophilic aromatic substitution. The origin of this discrepancy is discussed in detail. Possible mechanistic complications in the reaction leading to CIDNP are discussed. The laser CIDNP spectra of the Trp-rich peptides gramicidins A and B are presented as examples of the resolution enhancement obtained with this technique.

Evaluating interviewing techniques for the sexual practices history. Use of video trigger tapes to assess patient comfort.

BACKGROUND: Although physicians recognize the importance of assessing a patient's risk for human immunodeficiency virus (HIV) infection, many are reluctant to explore a person's sexual history, a principal determinant of this risk. OBJECTIVE: To examine the feasibility of a research design that uses responses to viewing a videotaped interview as a proxy for how patients might feel if they were interviewed using a specific approach, and to determine comfort levels with a variety of interview approaches for conducting HIV risk assessment. METHODS: Individuals responded to a videotape of several interviewing approaches for HIV risk assessment. Responses to the following aspects were collected: introduction of HIV risk assessment, assessment of patient comfort with the topic, techniques for collecting HIV risk and sexual information, and exploration of sensitive issues not previously identified. Participants expressed levels of comfort by means of a Likert scale to rate their comfort with each approach. RESULTS: Participants expressed higher comfort levels with an introduction that used a ubiquity statement or lifestyle bridge question. Also, they expressed greater comfort when the interviewer addressed how they felt about responding to questions about their HIV risk. Participants reported highest levels of comfort with both patient-centered and closed-ended interviewing techniques. Women were less comfortable with an open-ended interviewing technique. CONCLUSIONS: Individuals have different comfort levels for approaches used to assess HIV risk. This trigger tape experimental design to assess comfort levels for interview techniques is feasible for exploring other aspects of physician-patient communication; additional validation studies are recommended.

Chemically induced dynamic nuclear polarization studies of yeast tRNAPhe.

Chemically induced dynamic nuclear polarization (CIDNP) has been observed from yeast tRNAPhe following reaction with photoexcited riboflavin. At 20 degrees C, several resonances of tRNA in the native form show polarization; previous work predicts that only guanosine and its derivatives in single-stranded regions are likely to become polarized [ McCord , E.F., Morden , K. M., Pardi , A., Tinoco , I., Jr., & Boxer, S. G. (1984) Biochemistry (preceding paper in this issue)]. The methyl protons of m22G -26 show strong negative spin polarization, indicating that this residue is accessible. The solvent accessibility of this residue has not been previously demonstrated. In addition, two positively polarized aromatic resonances are observed, which are likely due to two or more G(H8) protons, including those of G-20, m22G -26, and/or Gm-34. For temperatures below 50 degrees C, a negatively polarized signal in the aromatic region is shown to arise from cross relaxation with the methyl group protons of m22G -26. This indicates the proximity of an aromatic proton, probably H2 of A-44, to the methyl groups of m22G -26. At higher temperatures, the CIDNP spectra show polarization of several additional G resonances, including those of m2G -10. These changes in the CIDNP spectra reflect melting of the tertiary and secondary structure of the tRNA. This work is the first use of CIDNP to study a large nucleic acid molecule and exemplifies the value of this technique in probing single-stranded and solvent-accessible regions of tRNA.