High-resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X-linked blue cone monochromacy.

The human X chromosome contains ∼ 1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases.

Chronic taurine supplementation ameliorates oxidative stress and Na+ K+ ATPase impairment in the retina of diabetic rats.

This study evaluates the effect of 4 months supplementation with 2% and 5% taurine (w/w) on the retina of diabetic rats. In non-diabetic rats, taurine does not modify glycemia, body weight, retinal conjugated dienes (CD), lipid hydroperoxide (LP), and Na(+)K(+)ATPase activity. In diabetic rat, at 2, 4, 8, 16 weeks following the onset of diabetes, retinal CD and LP are significantly and progressively increased, while pump activity is gradually and significantly reduced. In taurine supplemented diabetic rats, glycemia is not affected but lipid peroxidation is significantly decreased. Finally, taurine preserves ATPase activity being 5% more effective than 2% taurine. We conclude that taurine supplementation ameliorates biochemical retinal abnormalities caused by diabetes, thereby suggesting that taurine may have a role in the prevention of retinal changes in diabetes.

The use of dynamic posturography to detect neurosensorial disorder in IDDM without clinical neuropathy.

The main aim was to evaluate the relative importance of sensory interactions for postural stability in 45 patients with insulin-dependent diabetes mellitus (IDDM) with and without peripheral neuropathy. All subjects had normal electronystagmography. Dynamic posturography provides functional, selective testing of three sensory modalities in maintenance of balance, i.e., vestibular, visual, and somatosensory. The Sensory Organization Test (SOT) includes six test conditions during which the subject tries to maintain an upright stance with as little sway as possible. The subject stands on a movable platform facing a square visual surrounding, which can be rotated independently. The test is performed first with the eyes open, then with the eyes closed. The second component of posturography testing consists of the Motor Control Test (MCT) concerning motor responses routinely used in balance maintenance. Compared to control subjects, IDDM patients with peripheral neuropathy but not patients without neuropathy showed lower scores for test conditions SOT 1 (analysis of variance, ANOVA F = 8.3; Scheffe test: p = 0.0007), SOT 2 (F = 6.6; p = 0.004), SOT 3 (F = 3.4; p = 0.04), and SOT 6 (F = 3.4; p = 0.04). The muscle response latencies in MCT were prolonged for small forward perturbations (F = 4.6; p = 0.02) in neuropathic patients (148.3+/-14.2 ms) with respect to control subjects, but not in non-neuropathic patients with respect to control subjects (135.2+/-13.3 ms). Sural (r = 0.2; p = 0.002) and peroneal (r = 0.12; p = 0.02) nerve conduction velocities showed significant correlations with muscle response latencies of MCT for small forward perturbations. Our results suggest a subclinical dysequilibrium in IDDM patients with peripheral neuropathy. The results of dynamic posturography may reflect the impairment of the somatosensory system, rather than a specific lesion of vestibular and/or visual modalities.

Distortion-product otoacoustic emissions and selective sensorineural loss in IDDM.

OBJECTIVE: To provide information about possible subclinical damage of the cochlear outer hair cells (OHCs) by means of transiently evoked otoacoustic emissions (TEOAEs) and distortion-product otoacoustic emissions (DPOAEs) in subjects with IDDM. RESEARCH DESIGN AND METHODS: TEOAEs and DPOAEs were recorded in 47 IDDM patients with normal hearing and in age- and sex-matched nondiabetic subjects. Peripheral neuropathy was diagnosed by nerve conduction velocity (NCV) at the peroneal and surral nerves. RESULTS: A subclinical peripheral neuropathy was found in 15 diabetic patients. Mean TEOAE amplitude was found to be significantly reduced in diabetic patients with a reduced NCV (7.6 +/- 3.2 dB; Scheffé's test: P = 0.03), but not in those without neuropathy (9.5 +/- 4.3 dB), with respect to control subjects (11 +/- 3.1 dB). Neuropathic patients also showed mean reduced DPOAE amplitude values in the region of middle and high frequencies from 1,306 to 5,200 Hz (P < 0.05), whereas no difference was found at the lowest-frequency amplitudes. A frequency-selective reduction of DPOAEs was also found in non-neuropathic patients (P < 0.05) in the region of higher frequencies at 3,284, 4,126, and 5,200 Hz compared with control subjects. No correlations were found among duration of diabetes, HbA1c values, TEOAEs and DPOAEs. CONCLUSIONS: Our results suggest that IDDM patients show an early abnormality of the micromechanical properties of the OHCs. In IDDM patients without a subclinical peripheral neuropathy, damage is limited to the higher frequencies and can be detected only by DPOAEs, whereas in IDDM patients with neuropathy, damage also involves the middle range of frequencies and can be detected by TEOAEs and DPOAEs. Therefore, DPOAEs seem to be able to detect the earliest cochlear selective-frequency dysfunction in IDDM patients without peripheral neuropathy. DPOAEs appear to be of greater clinical interest than TEOAEs; the former seem to be frequency specific and can be recorded at any chosen frequency, including high frequencies.

Effects of a large supper on glucose levels the following morning in patients with type 2 diabetes.

Seventeen patients were studied to test the hypothesis that a large evening meal influences the fasting glucose level and glucose tolerance the following morning in patients with type 2 diabetes. Oral hypoglycemic agents were discontinued for 2 weeks. The baseline fasting plasma glucose levels were 12.3 +/- 0.9 mmol/L. Fasting and postprandial (post-Sustacal) glucose, insulin, and C-peptide measurements were performed the morning after the patients received three separate meal protocols spaced 1 week apart. The caloric distribution of the meal protocols was (1) 7 kcal/kg of ideal body weight breakfast and lunch and 14 kcal/kg supper (small supper); (2) 7 kcal/kg breakfast and lunch and 28 kcal/kg for supper (large supper); and (3) 14 kcal/kg breakfast and lunch (no supper). Fasting glucose level were higher the morning after the large supper compared to no supper (13.6 +/- 0.7 versus 12.3 +/- 0.5 mmol/L, p < 0.05) and also to the small supper (13.6 +/- 0.7 versus 12.5 +/- 0.6 mmol/L, p = 0.05). No difference was observed in the fasting glucose levels between the small supper and no supper (p > 0.2). The fasting insulin and C-peptide levels, and the post-Sustacal areas under the curve of glucose, insulin, and C-peptide did not differ among the meals. In patients with type 2 diabetes, a large evening meal is associated with a modest elevation in fasting glucose the following morning.

Cochlear dysfunction in IDDM patients with subclinical peripheral neuropathy.

OBJECTIVE: To investigate the function of the auditory pathway from the cochlea to the auditory cortex in subjects with IDDM. RESEARCH DESIGN AND METHODS: Brain stem, middle-, and long-latency auditory-evoked responses and evoked otoacoustic emissions were measured in 48 normally hearing IDDM patients and in age- and sex-matched nondiabetic subjects. Peripheral neuropathy was diagnosed by nerve conduction velocity (NCV) at the peroneal and sural nerves. Auditory brain stem responses (ABRs) reflect auditory pathway function within the brain stem; middle-latency responses (MLRs) and long-latency responses (LLRs) originate from the auditory cortex; and evoked otoacoustic emissions (EOAEs) give objective information about preneural, mechanical elements of the cochlear function. RESULTS: A subclinical peripheral neuropathy was found in 12 diabetic patients. We found higher latencies of waves I (t = 4.4, P < 0.0001), III (t = 3.7, P = 0.0004), and V (t = 2.7, P = 0.008) of ABRs in diabetic patients (I: 1.7 +/- 0.13 ms; III: 3.9 +/- 0.17 ms; V: 5.7 +/- 0.24 ms), compared with those of the control group (I: 1.6 +/- 0.13 ms; III: 3.7 +/- 0.18 ms; V: 5.6 +/- 0.17 ms). However, neither central transmission time (i.e., the wave interpeak I-V) nor MLRs and LLRs were found to be significantly different in diabetic and control subjects. Mean EOAE amplitude was found to be significantly reduced (F = 4.2, P = 0.02) in diabetic patients with a reduced NCV (7.6 +/- 3.9 dB; Scheffé test: P = 0.03), but not in those without neuropathy (9.1 +/- 4.2 dB), compared with the control group (10.8 +/- 3.1 dB). No correlations were found between duration of diabetes and EOAEs or between sural NCV and peroneal NCV and metabolic control. EOAEs were not correlated with peroneal and sural NCVs. CONCLUSIONS: Our results indicate that the early preneural dysfunction of cochlear receptors causes a prolonged activation of the peripheral portion of the auditory pathway, while signal conduction along the central auditory pathway was shown to be normal in diabetes.

Nutrition interventions for intensive therapy in the Diabetes Control and Complications Trial. The DCCT Research Group.

As part of an intensive treatment regimen that had as its goal achieving and maintaining blood glucose levels in the normal range in individuals with insulin-dependent diabetes mellitus, dietitians in the Diabetes Control and Complications Trial implemented varying nutrition intervention strategies to counsel patients to attain normoglycemia. Dietary management encompassed recommendations on altering insulin dosages for varying food intake. Nutrition intervention was tailored to best meet a participant's life-style, motivation, ability to grasp information, diet history, and specific intensive insulin therapy. Dietitians were integral participants in the team management of individuals in the intensive treatment group. Selected nutrition interventions--Healthy Food Choices, exchange systems, carbohydrate counting, and total available glucose--and behavior management approaches were coupled with intensive insulin therapy. Case presentations illustrate each nutrition intervention in the attainment of normoglycemia.

Reduction in cardiovascular risk factors with intensive diabetes treatment in insulin-dependent diabetes mellitus.

We measured plasma lipid and lipoprotein levels at baseline and at 6-mo intervals in 47 normolipidemic patients with classic insulin-dependent diabetes mellitus treated either with a conventional (n = 21) or intensive (n = 26) diabetes-treatment program. Patients were followed for a mean of 3 yr (range 1-4 yr). Intensive diabetes treatment resulted in a significant improvement in glycemic control that caused sustained changes in plasma lipid and lipoprotein levels that were not evident with the conventional-treatment program. These changes, which persisted for periods averaging 3 yr, can potentially reduce predicted risk for the development of premature atherosclerosis. Thus, long-term near normoglycemia may have a role in the prevention of atherosclerosis in insulin-dependent diabetic patients.

Effect of dietary animal and vegetable protein on gallstone formation and biliary constituents in the hamster.

A gallstone-inducing diet was utilized to examine the effect of dietary proteins (casein, soybean and cottonseed) on gallstone formation. Casein produced gallstones in 100% of the animals; however, soybean or cottonseed proteins reduced gallstone incidence to 32% and 0%, respectively. In an effort to ascertain the mechanisms responsible for gallstone formation, serum cholesterol and the 3 primary biliary constituents (bile acids, phospholipids and cholesterol) were measured. Casein produced a 4-fold increase in biliary cholesterol, whereas soybean and cottonseed yielded a 3- and 2-fold increase, respectively, when compared to a commercial diet (Purina, no. 5001). Serum cholesterol was reduced by substituting dietary vegetable protein for animal protein. This study suggests that substitution of vegetable for animal protein in the diet can decrease gallstone formation in hamsters. It is proposed that this reduced gallstone formation is due to the decreased concentrations of biliary cholesterol induced by dietary modification.