Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls.

AIMS: KCNJ11-related diabetes is the most common form of permanent neonatal diabetes and has been associated with a spectrum of neurodevelopmental problems. We compared neurodevelopmental outcomes in patients with KCNJ11 mutations and their sibling controls. METHODS: Through our Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/), we evaluated 23 patients with KCNJ11 mutations with (n = 9) and without (n = 14) global developmental delay successfully treated with sulfonylurea and 20 healthy sibling controls, using a battery of targeted neuropsychological and behavioural assessments with scaled scores that are comparable across a wide range of ages. RESULTS: Patients with KCNJ11-related diabetes without global developmental delay had significant differences compared with sibling controls on a range of assessments including IQ, measures of academic achievement and executive function. KCNJ11 patients with global delay exhibited significant differences in behavioural symptoms with a tendency to avoid social contact and displayed a reduced ability to adapt to new circumstances. Parents reported more immature behaviour, gross mood swings, bizarre thoughts, other unusual and severe behaviours, and there were also significant deficits in all subdomains of daily living skills. CONCLUSIONS: This series represents the largest and most comprehensive study of neuropsychological and behavioural dysfunction of individuals with KCNJ11 diabetes and is the first to compare outcome with sibling controls. Our data demonstrate the variety of neurodevelopmental problems seen in those with KCNJ11 mutations, even in those without recognized global developmental delays. These data can be used to counsel families and guide structured neurodevelopmental assessments and treatments based on the initial genetic diagnosis in patients with neonatal diabetes.

Successful rhIGF1 treatment for over 5 years in a patient with severe insulin resistance due to homozygous insulin receptor mutation.

BACKGROUND: Congenital insulin resistance syndromes are caused by biallelic mutations within the insulin receptor gene (INSR). Recombinant human insulin-like growth factor (rhIGF1) has been used with mixed success; however, rigorous assessment of its efficacy is lacking. Here, we describe a child with a homozygous mutation in INSR successfully treated with rhIGF1 for more than 5 years. CASE REPORT: The patient presented with osmotic diabetes symptoms and was noted to have dysplastic dentition, hypertrichosis, coarse and dysmorphic facial features. Acanthosis nigricans, skin tags and rugated hyperkeratosis were also evident on the posterior neck, axilla and groin. A homozygous INSR essential splice site mutation (c.1268 + 2T > C, p.G374 fs*12) was identified, for which both parents were found to be heterozygous. The patient was treated with twice daily injections of rhIGF1 and metformin for more than 5 years with improvement in her acanthosis nigricans, hyperkeratosis and hypertrichosis. A dramatic fall in fasting insulin, HOMA-IR and HbA1c has been maintained over the entire course of treatment without adverse effects. Her linear growth velocity has remained on target for her predicted adult height. DISCUSSION: Our case demonstrates the effectiveness of rhIGF1 as an early treatment in a patient with a biallelic mutation within INSR without evidence of fluid retention, retinopathy, muscle pain, heart failure, cerebral infarcts or benign intracranial hypertension. Her case suggests rhIGF1 can and should be considered as an initial treatment option instead of as a final option in those with INSR mutations.

Adolescent non-adherence reveals a genetic cause for diabetes.

BACKGROUND: Glucokinase related maturity-onset diabetes of the young (GCK-MODY) is a form of monogenic diabetes characterized by mildly elevated fasting blood sugars and HbA(1c) typically ranging from 38 to 60 mmol/mol (5.6-7.6%). It is frequently unrecognized or misdiagnosed as Type 1 or Type 2 diabetes, resulting in unnecessary pharmacologic therapy. CASE REPORT: Two brothers were initially diagnosed with Type 1 diabetes mellitus. The brothers were maintained on a total daily insulin dose of 0.3-0.5 units/kg/day and had HbA(1c) values of 40-51 mmol/mol (5.8-6.8%) throughout childhood. After over 10 years of insulin treatment, the younger brother chose to discontinue his insulin therapy without informing his family or his clinician. Following cessation of insulin treatment, he did not experience any change in overall glycaemic control. Subsequent research-based genetic testing revealed a deleterious mutation in GCK in both brothers (p.Val182Met). The older brother subsequently discontinued insulin therapy and both have remained off all pharmacological therapy with good glycaemic control (HbA(1c) < 53 mmol/mol, < 7%) and no adverse complications. The family was advised to seek confirmatory genetic testing in the father and other relatives with hyperglycaemia. CONCLUSION: The family described above exemplifies the rationale behind considering a genetic cause when evaluating every person with new-onset hyperglycaemia or those with atypical diabetes. The cost of genetic testing for the most common MODY causing genes may be offset by savings made in therapeutic costs. It is important that all clinicians supervising diabetes care recognize the cardinal features that distinguish GCK-MODY from other forms of diabetes.

Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach.

Single gene mutations that primarily affect pancreatic ß-cell function account for approximately 1-2% of all cases of diabetes. Overlapping clinical features with common forms of diabetes makes diagnosis of monogenic diabetes challenging. A genetic diagnosis often leads to significant alterations in treatment, allows better prediction of disease prognosis and progression, and has implications for family members. Currently, genetic testing for monogenic diabetes relies on selection of appropriate individual genes for analysis based on the availability of often-limited phenotypic information, decreasing the likelihood of making a genetic diagnosis. We thus developed a targeted next-generation sequencing (NGS) assay for the detection of mutations in 36 genes known to cause monogenic forms of diabetes, including transient or permanent neonatal diabetes mellitus (TNDM or PNDM), maturity-onset diabetes of the young (MODY) and rare syndromic forms of diabetes. A total of 95 patient samples were analyzed: 19 with known causal mutations and 76 with a clinically suggestive phenotype but lacking a genetic diagnosis. All previously identified mutations were detected, validating our assay. Pathogenic sequence changes were identified in 19 out of 76 (25%) patients: 7 of 32 (22%) NDM cases, and 12 of 44 (27%) MODY cases. In 2 NDM patients the causal mutation was not expected as consanguinity was not reported and there were no clinical features aside from diabetes. A 3 year old patient with NDM diagnosed at 3 months of age, who previously tested negative for INS, KCNJ11 and ABCC8 mutations, was found to carry a novel homozygous mutation in EIF2AK3 (associated with Wolcott-Rallison syndrome), a gene not previously suspected because consanguinity, delayed growth, abnormal bone development and hepatic complications had not been reported. Similarly, another infant without a history of consanguinity was found to have a homozygous GCK mutation causing PNDM at birth. This study demonstrates the effectiveness of multi-gene panel analysis in uncovering molecular diagnoses in patients with monogenic forms of diabetes.

Platelet reactivity in type 2 diabetes mellitus: a comparative analysis with survivors of myocardial infarction and the role of glycaemic control.

UNLABELLED: Patients with type 2 diabetes mellitus exhibit considerable platelet dysfunction, though this is poorly characterized in patients with diabetes taking aspirin for the primary prevention of cardiovascular events. We sought to compare platelet function in this patient population with that of a high-risk group of non-diabetic subjects with a history of previous myocardial infarction (MI), and to assess whether glycaemic control impacts on platelet function. METHODS: Platelet aggregation was measured in response to incremental concentrations of five platelet agonists using light transmission aggregometry. All patients were taking aspirin, and aspirin insensitivity was defined as ≥ 20% arachidonic acid (AA) mediated aggregation. Patients with diabetes were divided according to glycaemic control (HbA(1c)): optimal ≤ 6.5, good 6.6-7.4 and suboptimal ≥ 7.5%. RESULTS: In total, 85 patients with type 2 diabetes and 35 non-diabetic patients with previous MI were recruited. Compared to MI patients, diabetes patients had increased aggregation in response to multiple concentrations of epinephrine, collagen, adenosine diphosphate and AA. Aspirin insensitivity was more common in type 2 diabetes (15% vs. 0%, p=0.037). Platelet aggregation was increased in response to several agonists patients with suboptimal glycaemic control compared to patients with optimal control. Aspirin insensitivity was also more common in patients with suboptimal glycaemic control compared to those with good or optimal control (26.0% vs. 8.3% vs. 4%, p=0.04). CONCLUSION: Patients with type 2 diabetes mellitus, without proven vascular disease, exhibit platelet dysfunction and have increased platelet aggregation and aspirin insensitivity compared to non-diabetic patients with previous MI. Platelet dysfunction in diabetes is more severe in patients with suboptimal glycaemic control.

Clinical significance of intrasubstance meniscal lesions on MRI.

Grade 2 meniscal changes on MRI are linear signals confined within the meniscus thought to represent areas of meniscal degeneration or intrasubstance tears. It has been reported that in only 10% of cases is a meniscal tear detected during subsequent arthroscopy. Usually non-operative management is appropriate, but in some cases, grade 2 meniscal changes are seen on MRI in patients with a typical presentation of a meniscal tear. In this circumstance, an arthroscopic partial meniscectomy may be indicated and an MRI report, which describes the meniscus as being normal, may be confusing. A pilot study of 10 consecutive symptomatic patients (mean age 28.1 years) with a grade 2 meniscal signal on MRI was performed. At arthroscopy, with thorough examination of the meniscus using a probe, an intrasubstance tear was detected in all 10 patients. Partial meniscectomy was performed, with a mean follow-up of 6.7 months. All but one patient (due to other pathology) had marked improvement in pain and function. Thus, the authors believe that grade 2 signal changes should be reported in a manner that raises the possibility that they may cause symptoms and that the presence of any intrasubstance changes should be clearly conveyed in the report.

Spatial orientation adjustments in children with autism in Hong Kong.

Abnormal spatial orientation and body postures in children with autism often interfere with visual abilities to attend tasks and social interactions. Twenty-four children diagnosed with autism from Kowloon, Hong Kong were assessed for spatial orientation and spatial management abilities. Positive changes in spatial orientation were evident when the children wore ambient prism lenses and included changes in posture from slanted to erect. Adjustments in spatial management were evident in improved ball catching ability, a task requiring visual tracking and eye-hand coordination. The findings suggest that alterations to the sensory systems may lead to behavioral change in some children.

Machine classification of dental images with visual search.

RATIONALE AND OBJECTIVES: The authors performed this study to assess the performance of a computer-based classification system that uses gaze locations of observers to define the subspace for machine learning. MATERIALS AND METHODS: Thirty-two dental radiographs were classified by an expert viewer into four categories of disease of the periapical region: no disease (normal tooth), mild disease (widened periodontal ligament space), moderate disease (destruction of the lamina dura), and severe disease (resorption of bone in the periapical area). There were eight images in each category. Six observers independently viewed the images while their eye gaze position was recorded. They then classified the images into one of the four categories. A sample of image space was used as input to a machine learning routine to develop a machine classifier. Sample space was determined with three techniques: visual gaze, random selection, and constrained random selection. K analyses were used to compare classification accuracies with the three sampling techniques. RESULTS: With use of the expert classification as a standard of reference, observers classified images with 57% accuracy, and the machine classified images with 84% accuracy by using the same gaze-selected features and image space. Results of kappa analyses revealed mean values of 0.78 for gaze-selected sampling, 0.69 for random sampling, 0.68 for constrained random selection, and 0.44 for observers. The use of sample space selected with the visual gaze technique was superior to that selected with both random-selection techniques and by the observers. CONCLUSION: Machine classification of dental images improves the accuracy of individual observers using gaze-selected image space.

A signal detection theory analysis of gap detection in the rat.

An innocuous sensory event (a prestimulus) briefly preceding a startle-eliciting stimulus (SES) reduces the amplitude of the elicited reflex. This study used signal detection theory (SDT) techniques to quantify the effects of gaps (pauses in otherwise continuous noise) on the rat's acoustic startle reflex. Sixteen rats were given four identical test sessions consisting of the randomized presentation of 150 trials of the SES alone and 150 trials of a gap-and-SES combination. Gap duration (1, 2, 4, and 8 msec) varied between sessions. Data analyses based on amplitude, difference scores, percentage scores, and SDT techniques identified similar patterns. The three longest gaps, but not the shortest, were reliably detected, and differences among these three were identified with percentage and SDT analyses. Analyses of amplitude changes over test sessions yielded different patterns for each measure. The results demonstrate that an SDT analysis is a sensitive index of prestimulus effects.

Postural orientation modifications in autism in response to ambient lenses.

Autistic children often display abnormal postures, head tilts, and other spatial management dysfunctions. Methods were introduced to measure spatial orientation in tasks in a group of fourteen autistic children in Montreal, Canada. Ambient lenses were found to improve posture, correct head tilts, and improve ball catching abilities. A model of spatial orientation is described and recommendations are made to incorporate ambient lenses in treatment programs.

Visual perceptual dysfunction in patients with schizophrenic and affective disorders versus control subjects.

Visual perception was evaluated with standard tests for 26 hospitalized patients with schizophrenia, 23 hospitalized patients with affective disorders, and 60 control subjects. Both patient groups differed significantly from the control group on low amplitude of accommodation, esophoria or exophoria, vergence duction suppression, and convergence and divergence recovery ductions. Only the affective group showed significantly reduced fusion at near distance, and only the schizophrenic group differed significantly from control subjects on disorganized left apex formation. These findings appear to confirm the presence of visual perceptual disorders that can cause disability in psychiatric patients, with important research and rehabilitation implications.

Limitations in distinguishing malignant from benign lesions of the breast by systematic review of mammograms.

Our objective was to assess whether or not a systematic review of mammographic descriptors would result in improved classifications of nonpalpable lesions of the breast and reductions of biopsies for benign conditions. The prelocalization mammograms of 200 consecutive patients who had 231 biopsies were reviewed in random order by four radiologists experienced in mammography. Each reader assessed the presence of 32 specific descriptors regarding masses and calcifications. The following descriptors were highly associated with malignancy: for masses, inhomogeneous density; irregular shape; spiculated borders; and for calcifications, many calcifications; microcalcifications; linear or branching patterns, or both, and high spatial density. For masses, the descriptors highly associated with benignity were homogeneous density, oval shape and sharp or lobulated borders. For calcifications, the descriptors highly associated with benignity were solid, round and irregularly shaped. Readers indicated their over-all rating of each lesion, ranging from definitely benign to definitely malignant. Ratings were compared with the findings of pathologic reports (181 benign to 50 malignant), and receiver operating characteristic analyses were performed. The areas under the curves (A[z]) varied from 0.65 to 0.78. If biopsies had not been performed on those patients who were judged to have most likely benign lesions, one could reduce the number of biopsies for benign conditions by 48 to 69 per cent; however, 18 to 46 per cent of the malignancies would be missed. We conclude that diagnoses based on a systematic review of descriptors are not sufficiently accurate to reduce the number of mammary biopsies.

Limited correlation of left ventricular end-diastolic pressure with radiographic assessment of pulmonary hemodynamics.

Left ventricular end-diastolic pressure (LVEDP) is a reliable indicator of the diastolic function of the left ventricle. The purpose of this study was to correlate the radiographic assessment of pulmonary hemodynamics with LVEDP. The study population consisted of 104 consecutive patients with four categories of LVEDP: less than 13 mm Hg (n = 26), 13-19 mm Hg (n = 30), 20-24 mm Hg (n = 24), and more than 24 mm Hg (n = 24). Chest radiographs obtained within 24 hours of cardiac catheterization were assessed for evidence of congestive heart failure (CHF) by three experienced radiologists. Findings were graded from 0 to 3 (normal to abnormal) on the basis of the following signs of CHF: redistribution, perihilar and perivascular haze, peribronchial cuffing, pulmonary artery-bronchus ratio, septal lines, subpleural edema, air-space edema, pleural effusion, cardiomegaly, and overall radiographic assessment of CHF. A consensus report was then generated. In patients with LVEDP over 20 mm Hg, 38% did not show CHF in the overall assessment. Correlation between radiographic signs of CHF and LVEDP was limited.

Wife assault and perceptions of sanctions.

Using survey data based on telephone interviews of 1,626 coupled males, this study explores the relationship between perceptions of four possible sanctions for wife assault and involvement in this form of physical aggression. The exploratory analysis addresses the following questions: To what extent do men perceive negative reactions to wife assault as certain and severe? Do nonassaultive men perceive the reactions of others as more certain and severe than men who engage in physically aggressive behavior? Among men who assault their partners, are the perceived certainty and severity of sanctions greater for one-time offenders than for repeat offenders? The relevance of the findings on the deterrent and experimental effects of sanctions are discussed, and suggestions are offered for future studies that apply deterence theory to the phenomenon of assaults taking place between adult partners.

Nodule detection with and without a chest image.

The detectability of nodules displayed on uniform backgrounds was compared with their detectability on chest images by using receiver operating characteristic (ROC) curves. The images were displayed using a digital television system. Two conditions, chest image and uniform background, were compared at three different levels of added random noise. The viewing conditions were made as similar as possible by setting the luminance of the uniform background equal to the luminance of the lung in the chest image. Nodule detectability was significantly lower for the chest image than for the uniform background at each level of added random noise. The anatomic structure of the chest image interferes with the structural integrity of the nodule image resulting in lower detection performance.

Comparison scans while reading chest images. Taught, but not practiced.

Radiology instructors and residents were surveyed for their methods of instruction concerning viewing techniques. A similar group of radiologists had their eye activity measured as they viewed chest images. Image reading techniques are taught to be systematic and directive with comparisons of bilateral features. Yet, most images are read by a free search method; bilateral comparisons comprise less than 4% of the visual activity. Instructors and residents show this discrepancy between instructional techniques and reading practice.

Post tonsillectomy haemorrhage.

In a review of 3,756 cases of tonsillectomy the incidence of reactionary and secondary haemorrhage was the same-1 per cent. Both types of haemorrhage were commoner in adults. In the 10-19 age group, significantly more females than males had secondary bleeding. Although the majority occurred during the winter months, no patient with secondary haemorrhage had obvious respiratory tract infection. The use of diathermy at operation, while associated with a higher rate of secondary bleeding, significantly reduced the number of reactionary haemorrhages which are responsible for a high proportion of post-tonsillectomy fatalities.