Differential Effects of Anionic,Cationic, Nonionic,and Physiologic Surfactants on the Dissociation, α-Chymotryptic Degradation,and Enteral Absorption of Insulin Hexamers

Various surfactants were investigated to compare their effects on insulin dissociation, -chymotryptic degradation, and rat enteral absorption. With a circular dichroism technique, sodium dodecyl sulfate (SDS) at a 5 mM concentration was found to completely dissociate procine-zinc insulin hexamers (0.5 mg/ml) into monomers. The catalytic activity of -chymotrypsin (0.5 µM) was also abolished by 5 mM SDS. When insulin was injected into the distal jejunum/ proximal ileum segment of the rat, 5 mM SDS greatly enhanced its pharmacological availability, from a negligible value to 2.8%. Being a cationic surfactant, hexadecyl trimethylammonium bromide (CTAB) also efficiently dissociated insulin hexamers at concentrations of 1–5 mM. However, extensive charge–charge interaction was observed below a CTAB concentration of 0.6 mM, leading to insulin precipitation at a molar CTAB:insulin ratio of 1:1 to 2:1. An -chymotryptic degradation study also revealed near-complete dissociation of insulin hexamers at 1 mM CTAB. Above 1 mM, however, CTAB acted as an enzyme inhibitor, most likely by means of charge repulsion. Enteral absorption studies showed a much lower pharmacological availability, only 0.29%. Nonionic surfactants such as Tween 80 and polyoxyethylene 9 lauryl ether were ineffective in dissociating insulin hexamers. Tween 80, at 5 mM, neither significantly altered the -chymotryptic degradation pattern nor enhanced the enteral absorption of insulin. The relative effectiveness of different species of bile salts on insulin hexamer dissociation appeared to be similar. Sodium glycocholate at a 30 mM concentration also significantly increased insulin pharmacological availability, to 2.3%. A morphological study did not reveal any significant alteration of the rat intestinal mucosal integrity after exposure to 5 mM SDS for 30 min. The results further emphasize the importance of the degree of insulin aggregation on its enteral transport.     

Switching to darunavir/ritonavir 800/100 mg once‐daily containing regimen maintains virological control in fully suppressed pre‐treated patients infected with HIV‐1

The objective of this study was to evaluate the switch to once‐daily darunavir/ritonavir 800/100 mg in treatment‐experienced patients with suppressed HIV‐1 replication on a twice‐daily ritonavir‐boosted protease‐inhibitor (bid PI/r) containing regimen, that is in a setting where genotypic resistance test cannot be performed. In this open label, non‐comparative, multicenter study, patients on a bid PI/r‐containing triple combination, with suppressed viral replication, were switched to once‐daily darunavir/r 800/100 mg containing triple combination. The primary endpoint was the proportion of patients with plasma HIV‐RNA < 50 copies/ml 24 weeks after the switch. Intensive darunavir pharmacokinetic evaluation was performed at Week 4 (W4) in 11 patients. Eighty‐five patients were enrolled. All had HIV‐RNA < 50 copies/ml at screening with a pre‐exposure to a median of 2 PI/r (1–5). By intent‐to‐treat analysis (missing = failure), 78/85 patients (92%, 95% CI [83;96]) maintained an HIV‐RNA < 50 copies/ml at W24. Seven patients experienced protocol‐defined treatment failure between baseline and W24: Two had confirmed low‐level viral rebound, one discontinued study treatment for adverse event, three withdrew their consent, and one was lost to follow‐up. By on‐treatment analysis, 78/80 patients (97%, 95% CI [91;99]) maintained an HIV‐RNA < 50 copies/ml at W24. Results were similar at Week 48. The median area under the darunavir plasma concentration–time curve measured in 11 patients was 61,380 ng hr/ml; darunavir median trough concentration 1,340 ng/ml and darunavir half‐life was 12.2 hr. Tolerability of once‐daily darunavir/r 800/100 mg was excellent. Optimally suppressed, treatment‐experienced patients can switch safely from a twice‐daily PI/r regimen to a once‐daily darunavir/r 800/100 mg containing regimen. J. Med. Virol. 85:8–15, 2012. © 2012 Wiley Periodicals, Inc.     

Development of a multiplex,PCR-based genotyping assay for African and Asian elephants for forensic purposes

International Journal of Legal Medicine - Wildlife crimes and the threats they present to elephant populations raise the need to develop and implement DNA-based methodology as an aid for wildlife...     

Nonmodularity of the central auditory nervous system: implications for (central) auditory processing disorder

This response to A. T. Cacace and D. J. McFarland (2005) identifies points of agreement and disagreement regarding the concept of modularity in the diagnosis of (central) auditory processing disorder [(C)APD]. We concur that the evaluation of (C)APD must take into consideration the influence of higher order global or pansensory issues on performance on tests of central auditory function. To accomplish this goal, multidisciplinary (e.g., multimodal) testing is an integral part of differential diagnosis of (C)APD. We also agree that the efficiency of diagnostic tests of (C)APD should not be evaluated by imprecise criteria [e.g., "presumed" or "suspected" (C)APD], which do not provide accurate measures of the true sensitivity and specificity of these tests. Our conceptualization and recommendations for clinical practice in this area diverge, however, from that of Cacace and McFarland in a number of pivotal ways. Based on the current limitations of multimodal assessment relative to issues related to scope of practice and test efficiency, as well as the accumulated basic science and clinical literature that demonstrates the nonmodularity and interactive organization of the brain, we recommend use of the sensitized test battery of the central auditory nervous system (CANS) in combination with multidisciplinary testing to differentially diagnose (C)APD and to guide treatment of the disorder. We assert that sensitivity and specificity measures derived from individuals with well-circumscribed lesions of the CANS provide an important guide to establishing the validity of central auditory diagnostic tests. We note that researchers in the area of auditory science and (C)APD must acknowledge the challenges of the clinical arena, and we encourage their continued help to develop diagnostic tools that are both efficient and practical for the differential diagnosis of (C)APD. We conclude that our approach, which combines multidisciplinary evaluation and specific tests of central auditory function that have demonstrated sensitivity and specificity for disorders of the CANS, allows us to identify (and thus rehabilitate) the auditory deficits present in individuals with (C)APD in its "purest" form. It also permits the identification and rehabilitation of auditory deficits in individuals who exhibit auditory perceptual problems that coexist with other processing problems, while ruling out those who perform poorly on auditory tests because of a global, supramodal problem involving cognition, attention, language, memory, or related skills.     

Characteristics of temporary noise-induced tinnitus in male and female subjects

Reversible tinnitus was induced in 10 male and 8 female normal-hearing subjects following a 5 min 110 dB SPL exposure to white noise. Temporary threshold shift (TTS) was measured at 2 and 4 kHz. Characteristics of the tinnitus were determined by means of a written questionnaire administered 5 min following termination of the noise. Most of the subjects experienced a continuous tonal tinnitus of moderate loudness. Characterization of the tinnitus regarding spectral quality, type of sound, and perceived location differed as a function of gender. No difference in TTS measured at 2 and 4 kHz was seen as a function of gender. Positive relationships of fair to moderate strength were revealed between pre-exposure thresholds, TTS, and tinnitus pitch and level.     

Central deafness: a review of past and current perspectives

Abstract

Objective: The purpose of this review was to describe and differentiate clinical syndromes caused by lesions of the central auditory nervous system (CANS).

Design: Relevant literature was identified through Pubmed and Google Scholar searches using the key terms: central deafness, auditory agnosia, word deafness and cortical deafness. Given the authors’ intent to review past and current perspectives on central deafness, no publication date range was imposed.

Study sample: The review is organised around complete central deafness (CCD), central deafness (CD), word deafness and nonverbal agnosia (NVA), including anatomy and pathophysiology, symptom profile and audiological findings. Four case studies are presented to demonstrate the clinical correlates of CD.

Conclusions: Central deafness is a rare condition typically resulting from bilateral compromise of the CANS. The closer to the auditory cortex bilateral lesions are located, the greater the probability of CD. A variety of symptoms present with or appear subsequent to CD, including tinnitus, hallucinations, voice changes and hypersensitivity to sounds (if heard by the patient), as well as diverse neurological symptoms depending on the non-auditory areas of the brain that may also be involved. Thorough and appropriate audiological testing is critical to accurately diagnose CD and its variants.     

Treatment effects of the mandibular anterior repositioning appliance on patients with Class II malocclusion.

The mandibular anterior repositioning appliance (MARA) is a tooth-borne functional appliance for use in patients with Class II malocclusions; it positions the mandible forward into a Class I occlusion. The aim of this study was to investigate the MARA's dental and skeletal effects on anterior, posterior, and vertical changes in 30 Class II patients. The treatment group consisted of 12 boys with an average age of 11.2 years and 18 girls with an average age of 11.3 years. A pretreatment cephalometric radiograph was taken 2 weeks before treatment, and a posttreatment cephalometric radiograph was taken 6 weeks after removal of the MARA, with an average treatment time of 10.7 months. The mean and standard deviation were calculated for each cephalometric variable, and Student t tests were performed to determine the statistical significance of the changes. The results of the study showed that the MARA produced measurable treatment effects on the skeletal and dental elements of the craniofacial complex. These effects included a considerable distalization of the maxillary molar, a measurable forward movement of the mandibular molar and incisor, a significant increase in mandibular length, and an increase in posterior face height. The effects of the MARA treatment were then compared with those of the Herbst and Fr?nkel appliances. The treatment results of the MARA were very similar to those produced by the Herbst appliance but with less headgear effect on the maxilla and less mandibular incisor proclination than observed in the Herbst treatment group.     

Interlist equivalence of the word intelligibility by picture identification test administered in broad-band noise

The effect of broad-band noise on the interlist equivalence of the Word Intelligibility by Picture Identification Test (WIPI) was examined. Subjects were 24 normally hearing children aged 6:7-9:1 years (years:months) who were assigned in equal numbers to one of three signal-to-noise ratio (S/N) conditions (S/N = 0, +2, +4dBSPL). Each child was administered all four lists of the WIPI under one of these noise conditions. No significant order, gender or ear effects were observed. Performance increased linearly with increasing S/N. Statistically significant mean differences were seen between lists, and individual interlist pairwise comparisons revealed differences exceeding chance occurrence. Pooled correlations of interlist equivalence were of moderate strength. Caveats regarding clinical application of the WIPI administered in noise are discussed.     

Performance of American Indian children with fetal alcohol syndrome on the test of language development

Alcohol is a teratogen known to have deleterious effects on the developing embryo and fetus. Language deficits secondary to central nervous system dysfunction are among the sequelae of Fetal Alcohol Syndrome (FAS). Limited information is available regarding the language deficits associated with FAS, particularly among the population of American Indians in whom FAS is highly prevalent. The TOLD-P and TOLD-I were administered to 27 American Indian children: 10 with FAS and 17 normally developing control subjects. Pure-tone screening, immittance measurement, and vision screening preceded language testing. The older FAS children presented syntactic deficits while the younger FAS subjects presented more global language deficits.