Transgenic zebrafish model of the C43G human insulin gene mutation

Aims/Introduction

The human insulin gene/preproinsulin protein mutation C43G disrupts disulfide bond formation and causes diabetes in humans. Previous in vitro studies showed that these mutant proteins are retained in the endoplasmic reticulum (ER), are not secreted and are associated with decreased secretion of wild‐type insulin. The current study extends this work to an in vivo zebrafish model. We hypothesized that C43G‐green fluorescent protein (GFP) would be retained in the ER, disrupt β‐cell function and lead to impaired glucose homeostasis.

Materials and Methods

Islets from adult transgenic zebrafish expressing GFP‐tagged human proinsulin mutant C43G (C43G‐GFP) or wild‐type human proinsulin (Cpep‐GFP) were analyzed histologically across a range of ages. Blood glucose concentration was determined under fasting conditions and in response to glucose injection. Insulin secretion was assessed by measuring circulating GFP and endogenous C‐peptide levels after glucose injection.

Results

The majority of β‐cells expressing C43G proinsulin showed excessive accumulation of C43G‐GFP in the ER. Western blotting showed that C43G‐GFP was present only as proinsulin, indicating defective processing. GFP was poorly secreted in C43G mutants compared with controls. Despite these defects, blood glucose homeostasis was normal. Mutant fish maintained β‐cell mass well into maturity and secreted endogenous C‐peptide.

Conclusions

In this model, the C43G proinsulin mutation does not impair glucose homeostasis or cause significant loss of β‐cell mass. This model might be useful for identifying potential therapeutic targets for proper trafficking of intracellular insulin or for maintenance of β‐cell mass in early‐stage diabetic patients.     

Clinical assessment of the Zeiss IOLMaster

PURPOSE: To compare axial lengths and intraocular lens (IOL) power calculations obtained with the Zeiss IOLMaster by 2 observers with different training grades and to assess the agreement between optical and acoustic biometry. SETTING: Department of Ophthalmology, Pembury Hospital, The Laser Eye Clinic, Kent, United Kingdom. METHODS: In this prospective study, optical biometry was performed twice in 79 patients: first by a qualified ophthalmic nurse and second by 1 of several health care assistants without formal nursing training. In the same group of patients, the qualified nurse also obtained ultrasonic measurements to compare the 2 clinical methods. RESULTS: There was a high correlation coefficient for axial length and IOL power measurements (0.99 each) between the experienced examiner and the inexperienced examiners. The coefficient of repeatability (2 SD) was 0.58 diopter (D) for IOL power (mean 0.04 D) and 0.07 mm for the axial length (mean 0.00 mm). The correlation coefficient of IOLMaster measurements with A-scan measurements done by the same experienced ophthalmic nurse was 0.97 for IOL power and 0.98 for axial length. The limits of agreement (mean +/- 2 SD) were between +0.50 and -2.40 D for IOL power calculations and between +0.7 mm and -0.2 mm for axial length measurements. CONCLUSIONS: Optical biometry showed excellent repeatability using different examiners regardless of their medical training. The agreement with ultrasonic measurements and the precision of the method need further evaluation.     

Cochlear implantation in adults with unilateral deafness: A review of the assessment/evaluation protocols

Objectives: Cochlear implantation is becoming widely used outside the tertiary research centers for treatment of unilateral deafness (UD). No consensus exists, however, on the most suitable assessment/evaluation protocols for this group of adult patients. This paper aims to review the assessment and evaluation protocols used by various research groups and to propose a protocol for the use in the clinical setting.

Methods: The PubMed, Embase, and Cochrane Library databases were searched with the keywords ‘cochlear’, ‘implant’, ‘single-sided’, ‘deafness’, ‘adults’, ‘unilateral’, and ‘deafness’. The words were either used individually, combined in pairs, or in groups of 5. All articles reporting on prospective studies, retrospective studies, or case studies were included.

Results: Sixteen published studies met the inclusion criteria. Measures of hearing performance, tinnitus, subjective quality of hearing, and quality of life varied greatly among studies.

Discussion: Adaptive speech in noise testing, localization, tinnitus measurement questionnaires, and self-rated hearing improvement are widely used among the research groups. These tools in conjunction assess and evaluate the main issues associated with UD.

Conclusion: The test battery most commonly used to assess and evaluate adult cochlea implant users with UD consists of (a) a subjective self-rating of hearing performance, (b) localization testing, and (c) the adaptive speech in noise testing conducted in at least the following three spatial configurations: speech and noise presented from the front (S0/N0), speech presented from the front and noise presented to the good hearing ear (S0/Nhe), and speech presented to the implanted ear and noise presented to the hearing ear (Sci/Nhe).     

Metaanalysis of Survival,Complications, and Imaging Response following Chemotherapy-based Transarterial Therapy in Patients with Unresectable Intrahepatic Cholangiocarcinoma

PurposeUnresectable intrahepatic cholangiocarcinoma represents a devastating illness with poor outcomes when treated with standard systemic therapies. Several smaller nonrandomized outcomes studies have been reported for such patients undergoing transarterial therapies. A metaanalysis was performed to assess primary clinical and imaging outcomes, as well as complication rates, following transarterial interventions in this patient population.Materials and MethodsBy using standard search techniques and metaanalysis methodology, published reports (published in 2012 and before) evaluating survival, complications, and imaging response following transarterial treatments for patients with unresectable intrahepatic cholangiocarcinoma were identified and evaluated.ResultsA total of 16 articles (N = 542 subjects) met the inclusion criteria and are included. Overall survival times were 15.7 months±5.8 and 13.4 months±6.7 from the time of diagnosis and time of first treatment, respectively. The overall weighted 1-year survival rate was 58.0%±14.5. More than three fourths of all subjects (76.8%) exhibited a response or stable disease on postprocedure imaging; 18.9% of all subjects experienced severe toxicities (National Cancer Institute/World Health Organization grade≥3), and most experienced some form of postembolization syndrome. Overall 30-day mortality rate was 0.7%.ConclusionsAs demonstrated by this metaanalysis, transarterial chemotherapy-based treatments for cholangiocarcinoma appears to confer a survival benefit of 2–7 months compared with systemic therapies, demonstrate a favorable response by imaging criteria, and have an acceptable postprocedural complication profile. Such therapies should be strongly considered in the treatment of patients with this devastating illness.     

Insights in Public Health: The Childhood Obesity Prevention Task Force (ACT 269): Recommendations for Obesity Prevention in Hawai‘i

Obesity in both adults and children is a critical issue in Hawai‘i, as well as nationally and internationally. Today in Hawai‘i, 57 percent of adults are overweight or obese as are almost 1 in 3 children entering kindergarten. Each year, obesity costs Hawai‘i more than $470 million in medical expenditures alone.¹ These staggering human and economic costs underscore the serious need for Hawai‘i to address obesity now.Due to the urgent need to reverse the current trends in obesity Senate Bill 2778 was signed into law, on July 6, 2012, as Act 269 by Governor Neil Abercrombie, creating The Childhood Obesity Prevention Task Force. The task force was charged with developing policy recommendations and proposed legislation for the 2013 legislature. The task force ultimately identified eleven recommendations for the 2013 legislative session and one recommendation for the 2014 legislative session. When implemented together, these recommendations could profoundly reshape Hawai‘i''s school, work, community, and health care environments, making healthier lifestyles obtainable for all Hawai‘i residents.     

Treatment of uncomplicated gonorrhoea with rosoxacin (acrosoxacin)

An open study was designed primarily to evaluate the efficacy of rosoxacin in the treatment of gonorrhoea caused by penicillinase producing Neisseria gonorrhoeae (PPNG) and non-PPNG strains. A total of 199 patients (99 men and 100 women) satisfactorily completed follow up examinations, 50 men and 50 women having received rosoxacin 300 mg orally and the remainder having received kanamycin 2 g intramuscularly. Rosoxacin achieved an overall cure rate of 94% (96.7% for PPNG and 90% for non-PPNG strains). In patients treated with kanamycin the overall cure rate was 89.9% (92.7% for PPNG and 83.3% for non-PPNG strains). A correlation between treatment failures and minimum inhibitory concentrations (MICs) of rosoxacin was noted in non-PPNG strains but not in PPNG strains. Side effects which were mild and self limiting were noted in 15 of 100 patients treated with rosoxacin. The high failure rates associated with non-PPNG strains requiring MICs of 0.125 mg/l and the observation of a substantial rise in the MICs for isolates after treatment is of concern. Otherwise, rosoxacin in a single dose of 300 mg appears to be safe and effective for the treatment of uncomplicated gonorrhoea.     

Treatment of uncomplicated gonorrhoea with rosoxacin (acrosoxacin).

An open study was designed primarily to evaluate the efficacy of rosoxacin in the treatment of gonorrhoea caused by penicillinase producing Neisseria gonorrhoeae (PPNG) and non-PPNG strains. A total of 199 patients (99 men and 100 women) satisfactorily completed follow up examinations, 50 men and 50 women having received rosoxacin 300 mg orally and the remainder having received kanamycin 2 g intramuscularly. Rosoxacin achieved an overall cure rate of 94% (96.7% for PPNG and 90% for non-PPNG strains). In patients treated with kanamycin the overall cure rate was 89.9% (92.7% for PPNG and 83.3% for non-PPNG strains). A correlation between treatment failures and minimum inhibitory concentrations (MICs) of rosoxacin was noted in non-PPNG strains but not in PPNG strains. Side effects which were mild and self limiting were noted in 15 of 100 patients treated with rosoxacin. The high failure rates associated with non-PPNG strains requiring MICs of 0.125 mg/l and the observation of a substantial rise in the MICs for isolates after treatment is of concern. Otherwise, rosoxacin in a single dose of 300 mg appears to be safe and effective for the treatment of uncomplicated gonorrhoea.     

Cross sensitivity in colour developers

Colour developers are widely used and contact dermatitis and lichen planus-like eruptions from them are well-known. As a result of automation, there have been few recent reports of contact dermatitis from colour developers. We describe here 4 cases of dermatoses from Kodak CD4 colour developer and study their cross sensitivity to other colour developers and PPD. Attempts were made to determine the purity of the patch test allergens to ensure that cross sensitivity was not the result of contamination and decomposition of the allergens.     

Current management options for the small renal mass in a solitary kidney

The widespread use of cross-sectional imaging has resulted in an increase in the frequency of incidentally identified small renal masses (SRMs). With high cancer-specific survival rates following radical nephrectomy, there is an increasing patient cohort at risk of developing a metachronous contralateral tumour. Nephron-sparing surgery (NSS) has been shown to reduce progression of chronic kidney disease, being the impetus to utilize NSS for the management of SRMs in an anatomical or functional solitary kidney. At present, open partial nephrectomy is the gold standard treatment for an SRM in a solitary kidney; however, there are a number of other minimally invasive options, including laparoscopic partial nephrectomy, and in situ ablative procedures. In addition, variables such as warm and cold ischaemia and renal vascular clamping have been shown to affect outcomes. In this review, we summarize contemporary management options focusing specifically on oncological and functional outcomes.