Mutations of the human thyrotropin-beta subunit glycosylation site reduce thyrotropin synthesis independent of changes in glycosylation status.

In recent studies, site-directed mutagenesis has been used to alter the tripeptide glycosylation recognition sequences of glycoprotein hormone subunits, thereby affecting their structure and function. However, it is not known whether these effects result from changes in glycosylation status, amino acid sequence, or both. We therefore studied the synthesis of wild-type and mutant recombinant human thyrotropins produced by transient transfection of a human cell line. Mutating the TSH-beta subunit glycosylation recognition sequence, Asn-Thr-Thr (codons 23-25), to either Gln-Thr-Thr or Asn-Thr-Tyr abolished subunit glycosylation, as demonstrated by the inability to incorporate 3H-carbohydrates. However, a third mutation (Asn-Thr-Ser) contained an intact glycosylation recognition sequence site, and was shown to retain glycosylation. The mutations that abolished TSH-beta subunit glycosylation resulted in greater than 90% decreases in TSH synthesis. However, the glycosylation recognition sequence mutant that retained beta subunit glycosylation exhibited a 70% decrease in TSH production. These decreases were not attributable to the intracellular accumulation of TSH or its free beta subunit. We also engineered two TSH-beta subunit mutations that did not alter the glycosylation recognition sequence. A glycine to arginine mutation adjacent to the glycosylation recognition sequence, in a region thought to be critical for heterodimer formation, abolished TSH production. In contrast, shortening the TSH-beta subunit carboxyterminus by six amino acids increased TSH synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diabetes Education: Whose Priorities Are Met?

Two hundred Type 2 diabetic patients newly referred to the diabetes centre at a large university teaching hospital were studied over an 8-month period. Patients completed a diabetes knowledge questionnaire, and specified their educational priorities by selecting six diabetes-related topics from a list of 14. After giving 1 h of individual education and using the same list, the educators selected six topics which they considered to be most important for that particular patient to know. Choice of educational priorities differed between the patients and the corresponding educator (p less than 0.001). In only 38% of cases did the educators' first three priorities coincide with those of the patients. The major discrepancies were in the selection of 'sick day management' and 'complications', especially favoured by patients, as against 'oral hypoglycaemic agents' and other therapy-related topics, especially favoured by educators. Diabetes knowledge was a determinant of educational priority for patients (p less than 0.001) but not educators. In contrast, only the educators' overall choices were affected by duration of diabetes (p less than 0.001). Diabetes treatment type influenced both patients' and educators' selection of priorities (p less than 0.001). We conclude that an educational strategy which relies on health professionals' perceptions to determine what diabetic patients need to know may be inadequate.     

The synchronization of respiration and swallow sounds with videofluoroscopy during swallowing

Simultaneous recording of adult subjects sipping small amounts of fluid from a cup have been obtained by videofluoroscopy together with feeding respiratory patterns and swallow sounds from the Exeter Dysphagia Assessment Technique (EDAT). These allowed visual representations of respiration and swallow sounds to be superimposed on a videofluoroscopy recording using a split-screen technique. Sequentially numbered, 1/50 sec, half-frame photographic prints were examined and schematic drawings of the relevant radiographs were made. These were superimposed on to the actual EDAT printed chart of the same swallow event, theri exact time relationship with respiration and cervical swallow sounds being preserved. The results allow events in the barium videofluoroscopy to be related to events in the feeding respiratory pattern and swallow sounds recorded by EDAT.     

Suprasternal Doppler ultrasound for assessment of stroke distance

An assessment of a non-invasive technique for measurement of stroke distance was made using a portable Doppler ultrasound machine. The aim was to determine the measurement error of repeated stroke distance measurements (Within-observer variability) and to assess measurement agreement between two operators (between-observer variability). The measurement error (within-observer variability) for both operators was similar at approximately 2 cm. However, the measurements of the two operators (between-observer variability) did not agree well. Using the mean (SD) of three readings by each operator, the mean difference between the operators was -0.21 cm (1.96) giving a 95% confidence interval for the differences of -4.0 to +3.6 cm. There were significant positive and negative correlations between stroke distance and a variety of variables (age, height, weight, heart rate), but the relations were weak. The results indicate that the Doppler ultrasound technique for measurement of stroke distance would best be used to study trend changes in an individual patient, or subject, by a single operator.     

Prader–Willi Syndrome: A spectrum of anatomical and clinical features

Prader–Willi Syndrome (PWS) is estimated to affect 400,000 people worldwide. First described clinically in 1956, PWS is now known to be a result of a genetic mutation, involving Chromosome 15. The phenotypical appearance of individuals with the syndrome follows a similar developmental course. During infancy, universal hypotonia accompanied by feeding problems, hypogonadism, and dolichocephaly are evident. Characteristic facial features such as narrow bifrontal diameter, almond‐shaped eyes, and small mouth (with downturned corners and thin upper lip) may also be evident at this stage. In early childhood, the craniofacial features become more obvious and a global developmental delay is observed. Simultaneously, individuals develop hyperphagia that leads to excessive or rapid weight gain, which, if untreated, exists throughout their lifespan and may predispose them to numerous, serious health issues. The standard tool for differential diagnosis of PWS is genetic screening; however, clinicians also need to be aware of the characteristic features of this disorder, including differences between the genetic subtypes. As the clinical manifestations of the syndrome vary between individuals and become evident at different developmental time points, early assessment is hindered. This article focuses on the clinical and anatomical manifestations of the syndrome and highlights the areas of discrepancy and limitations within the existing literature. Clin. Anat. 29:590–605, 2016. © 2016 Wiley Periodicals, Inc.     

Lipid abnormalities and renal disease: is dyslipidemia a predictor of progression of renal disease?

Dyslipidemia is a cardiovascular disease (CVD) risk factor that is associated with enhanced atherosclerosis and plaque instability. Renal insufficiency is associated with abnormalities in lipoprotein metabolism in both the early and the advanced stages of chronic renal failure. These include alterations in apolipoprotein A (apo A)- and B- containing lipoproteins, high-density lipoproteins, and triglycerides. In animal models, these alterations in lipid metabolism and action lead to macrophage activation and infiltration in the kidney with resultant tubulointerstitial and endothelial cell injury. Limited data in humans suggest that, in addition to contributing to CVD, dyslipidemia may be a risk factor for the progression of renal disease. The effects of dyslipidemia on the kidney are mainly observed in those with other risk factors for renal disease progression such as hypertension, diabetes, and proteinuria. Renal disease is a strong risk factor for CVD and African Americans have high rates of renal disease. Therefore, examining the effects of dyslipidemia on the development or progression or renal disease will be an important question for the Jackson Heart Study and is the topic of this review.     

The rapidity of drug dose escalation influences blood pressure response and adverse effects burden in patients with hypertension: the Quinapril Titration Interval Management Evaluation (ATIME) Study. ATIME Research Group

BACKGROUND: Antihypertensive medication doses are typically increased within several weeks after initiation of therapy because of inadequate blood pressure (BP) control and/or adverse effects. METHODS: We conducted a parallel-group clinical trial with 2935 subjects (53% women, n=1547) aged 21 to 75 years, with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI stages 1 to 2 hypertension, recruited from 365 physician practices in the southeastern United States. Participants were randomized either to a fast (every 2 weeks; n=1727) or slow (every 6 weeks; n=1208) drug titration. Therapy with quinapril, an angiotensin-converting enzyme inhibitor, was initiated at 20 mg once daily. The dose was doubled at the next 2 clinic visits until the BP was lower than 140/90 mm Hg or a dose of 80 mg was reached. RESULTS: Pretreatment BP averaged 152/95 mm Hg. Patients with stage 2 hypertension reported more symptoms than those with stage 1. The BP averaged 140/86, 137/84, and 134/83 mm Hg in the slow group compared with 141/88, 137/85, and 135/84 mm Hg in the fast group at the 3 respective clinic visits. The BP control rates to lower than 140/90 mm Hg at the 3 clinic visits were (slow, fast, respectively) 41.3%, 35.7% (P<.001); 54.3%, 51.5% (P=.16); and 68%, 62.3% (P=.02). In the fast group, 10.7% of participants experienced adverse events vs 10.8% in the slow group; however, 21.0% of adverse events in the fast group were "serious" vs only 12% in the slow group. CONCLUSION: Slower dose escalation of the angiotensin-converting enzyme inhibitor quinapril provides higher BP control rates and fewer serious adverse events than more rapid drug dose escalation.     

Dysphagia in cerebral palsy: A comparative study of the exeter dysphagia assesment technique and a multidisciplinary assessment

Eighteen children with cerebral palsy in a special school, most of whom had feeding difficulties, were studied to compare the diagnostic value of the Exeter Dysphagia Assessment Technique (EDAT) with an exhaustive clinical assessment undertaken by a multidisciplinary team experienced in the diagnosis and treatment of dysphagia of neurological origin. Four feeding skills were assessed by each method independently, viz. anticipation, intraoral sensory perception, oral-motor efficiency, and pharyngeal triggering. Comparison of the two sets of results showed agreement in at least 78% of the assessed skills. The possible reasons for the few discrepancies are discussed. The noninvasive EDAT equipment was easy to use with the children, who had a range of type and severity of cerebral palsy. The test was undertaken in their familiar surroundings and took 15 to 20 min per child. Interpretation of the results showed that EDAT provided a rapid, reliable diagnostic aid which assisted in the assessment of the degree of feeding impairment within each of the four feeding skills tested. The authors are very grateful for the financial support for this project which was provided partially by Action Research and partially by the Northcott Devon Medical Foundation