A Case of Acromegaly With Progressed Diabetic Retinopathy and Sarcopenia Diagnosed Following the Onset of Severe Hypoglycemia.

Acromegaly is a rare disorder characterized by excessive production of growth hormone (GH) from a pituitary tumor, typically leading to elevated glucose levels due to increased insulin resistance; hypoglycemia is rare. However, the long-term effect of excess GH on the peripheral organs is still unclear. Here we present a 69-year-old man evaluated for the cause of a hypoglycemic episode. He was underweight (body mass index: 17.3 kg/m2) with sarcopenia, which potentially contributed to his hypoglycemia. Notably, he exhibited progressed proliferative diabetic retinopathy compared to other microvascular complications, leading to further endocrinological investigation. As a result, he was diagnosed with acromegaly showing elevated GH and insulin-like growth factor-1 (IGF-1) with a pituitary tumor. Opting against transsphenoidal surgery (TSS), the patient was treated with a somatostatin analog (SSA), achieving normalized IGF-1 levels with a monthly 120 mg lanreotide injection. In this case, acromegaly could lead to sarcopenia from GH-derived gluconeogenesis in the peripheral organs such as the reduction of muscle leading to reduced glucose reserves. Acromegaly in the elderly may present atypicality. Clinicians should be vigilant for unique manifestations such as advanced diabetic retinopathy, even in elderly patients with hypoglycemia.

Two Cases With Type 1 Diabetes Treated With Insulin Pump Therapy Using a Telemedicine Approach During the COVID-19 Pandemic.

Type 1 diabetes mellitus (T1D) is an autoimmune-related disease resulting in insulin dependency, treated with insulin injection via pen devices or continuous subcutaneous insulin infusion (CSII). Face-to-face instruction for managing insulin injection and dosing and machine-to-device troubleshooting are required early to initiate CSII from insulin injections. Thus, T1D individuals may encounter significant barriers to pen devices or CSII introduction if they live in remote rural areas. In this regard, intermittently scanned continuous glucose monitoring (isCGM) can share visualized glucose profiles via a cloud-platform-based system, offering the potential as an effective tool in telemedicine. Herewith, we report two cases of subjects with T1D living in remote rural areas whose CSII was safely introduced in outpatient settings with the aid of cloud-platform-based isCGM and a video-meeting tool. They showed improved glucose profiles after CSII initiation. Even under the coronavirus disease 2019 (COVID-19) pandemic, the telemedicine system enabled healthcare providers to monitor glucose profiles and confirm device procedures of CSII. We emphasize the usefulness of online instruction with cloud-platform-based isCGM for introducing CSII in cases with barriers to healthcare access, particularly during the COVID-19 pandemic.

Associations of age-adjusted coefficient of variation of R-R intervals with autonomic and peripheral nerve function in non-elderly persons with diabetes.

AIMS/INTRODUCTION: Early diagnosis of diabetes-associated cardiac autonomic neuropathy using the coefficient of variation of R-R intervals (CVRR) may improve outcomes for individuals with diabetes. The present study examined the associations of decreased CVRR at rest and during deep breathing (DB) with other autonomic nerve function parameters. MATERIALS AND METHODS: The electronic records of 141 inpatients with diabetes (22-65 years) admitted to our hospital between March 2015 and March 2019 were analyzed retrospectively. After assessment by exclusion criteria, 51 inpatients were included. All inpatients were assessed for peripheral and autonomic nerve function, clinical characteristics, and physical abilities. RESULTS: Inpatients with decreased CVRR at rest (n = 9 (17.6%)) and during DB (n = 12 (23.5%)) had a longer duration of known diabetes, a higher prevalence of diabetic retinopathy, lower body mass index (BMI), skeletal mass index (SMI), and knee extension strength, and a higher proportion of impaired standing balance. Decreased CVRR at rest was associated with a greater fall in diastolic BP from supine to standing, higher resting HR, longer QTc, longer time of voiding, and sensory symptoms. CONCLUSIONS: Decreased CVRR at rest and during deep breathing was associated with lower BMI, SMI, and knee strength and a higher proportion of impaired standing balance among non-elderly inpatients with diabetes. Decreased CVRR at rest appeared more strongly associated with a greater orthostatic BP decline, higher resting heart rate, longer QTc, lower urinary tract dysfunction, and sensory symptoms than a decreased CVRR during deep breathing.

Concurrent bacterial liver abscess and mild encephalitis/encephalopathy with reversible splenial lesion in a patient with poorly controlled type 2 diabetes.

A 34-year-old man with poorly controlled type 2 diabetes was admitted to our hospital because of fever, headache, vomiting, and impaired consciousness. His hemoglobin A1c level was as high as 11.0%. Abdominal computed tomography revealed a bacterial liver abscess, while head magnetic resonance imaging simultaneously showed a high-signal lesion on diffusion-weighted imaging and a low-signal lesion on the apparent diffusion coefficient map of the splenium of the corpus callosum. No significant findings were detected in the cerebrospinal fluid. The latter findings led to a diagnosis of mild encephalitis/encephalopathy with reversible splenial lesions. His impaired consciousness resolved on Day 5 after treatment with ceftriaxone and metronidazole infusion and intensive insulin therapy; magnetic resonance imaging on Day 20 showed that the lesion in the splenium of the corpus callosum had disappeared. We propose that when a person with poorly controlled diabetes develops a bacterial infection and presents with impaired consciousness and headache, clinicians should consider the complications of mild encephalitis/encephalopathy with reversible splenial lesion.

Long-term observation of estimated fluid volume reduction after the initiation of ipragliflozin in patients with type 2 diabetes mellitus: a sub-analysis from a randomized controlled trial (PROTECT).

BACKGROUNDS/AIM: Recent studies have shown that the addition of sodium-glucose co-transporter 2 (SGLT2) inhibitors gradually reduces the estimated fluid volume parameters in a broad range of patient populations, suggesting that this mediates the clinical benefits of SGLT2 inhibitors in preventing heart failure. Here, we sought to examine the long-term (24 months) effect of the SGLT2 inhibitor ipragliflozin on the estimated fluid volume parameters in patients with type 2 diabetes mellitus (T2DM). METHODS: In this prespecified sub-analysis of the PROTECT (Prevention of Atherosclerosis by SGLT2 Inhibitor: Multicenter, Randomized Controlled Study) trial, which was an investigator-initiated, multicenter, prospective, randomized, open-label, clinical trial primarily designed to evaluate the effect of ipragliflozin treatment administered for 24 months on carotid atherosclerosis in patients with T2DM, we evaluated serial changes in estimated plasma volume (ePV, %) calculated using the Straus formula and estimated extracellular volume (eEV, mL) calculated by the body surface area by 24 months following the initiation of 50-mg ipragliflozin once daily and compared them with those following standard care for T2DM (non-SGLT2 inhibitor use). RESULTS: This sub-analysis included 464 patients (ipragliflozin, n = 232; control, n = 232), a full analysis set of the PROTECT trial. In an analysis using mixed-effects models for repeated measures, relative to the control group, ipragliflozin significantly reduced ePV by - 10.29% (95% confidence interval [CI] - 12.47% to - 8.11%; P < 0.001) at 12 months and - 10.76% (95% CI - 12.86% to - 8.67%; P < 0.001) at 24 months. Additionally, ipragliflozin significantly reduced eEV by - 190.44 mL (95% CI - 249.09 to - 131.79 mL; P < 0.001) at 12 months and - 176.90 mL (95% CI - 233.36 to - 120.44 mL; P < 0.001) at 24 months. The effects of ipragliflozin on these parameters over 24 months were mostly consistent across various patient clinical characteristics. CONCLUSIONS: This prespecified sub-analysis from the PROTECT trial demonstrated that ipragliflozin treatment, compared with the standard care for T2DM, reduced two types of estimated fluid volume parameters in patients with T2DM, and the effect was maintained for 24 months. Our findings suggest that SGLT2 inhibitor treatment regulates clinical parameters incorporated into the calculating formulas analyzed and consequently fluid volume status for the long-term, and this may be at least partly associated with clinical benefits from chronic use of SGLT2 inhibitors. Trial registration Japan Registry of Clinical Trials, ID jRCT1071220089.

Longitudinal effects of one-leg standing time on neuropathy outcomes in association with glycemic control in non-elderly patients with type 2 diabetes.

AIMS/INTRODUCTION: Diabetic neuropathy leads to postural instability. This study compared longitudinal changes in neuropathy outcomes relative to long-term glycemic control in patients aged <60 years with uncontrolled type 2 diabetes with and without a short one-leg standing time (OLST <60 s). MATERIALS AND METHODS: In this retrospective study, 58 hospitalized patients with type 2 diabetes (glycated hemoglobin [HbA1c] >7.0%; aged 17-59 years), who underwent re-evaluation of neuropathic sensory symptoms, ankle reflexes and nerve conduction attributes, and cardiac autonomic function (R-R interval), >1 year after discharge were divided into OLST <60 and ≥60 s groups. Patients were followed up every 2-3 months for HbA1c levels for up to 8 years. Neuropathy outcomes relative to OLST and HbA1c levels at baseline and over follow up were compared. RESULTS: Additional development of sensory symptoms (one patient) and abnormal ankle reflexes (five patients) were identified during follow up, and decreased peripheral and cardiac autonomic function at both baseline and follow up, only in patients with OLST <60 s. Mean HbA1c levels were significantly higher in patients with OLST <60 s versus ≥60 s (7.8 ± 0.9% vs 7.2 ± 1.2%; P = 0.022). Better glycemic control during follow up was associated with better neuropathy outcomes only in patients with OLST ≥60 s. CONCLUSION: Non-elderly type 2 diabetes patients with OLST <60 s and decreased peripheral nerve function at baseline are at increased risk for intractable diabetic neuropathy. Better glycemic control alone might not improve neuropathy outcomes in these patients.

The Multi-Domain Intervention Trial in Older Adults With Diabetes Mellitus for Prevention of Dementia in Japan: Study Protocol for a Multi-Center, Randomized, 18-Month Controlled Trial.

Background: The Japan-Multi-domain Intervention Trial for Prevention of Dementia in Older Adults with Diabetes (J-MIND-Diabetes) is an 18-month, multi-centered, open-labeled, randomized controlled trial designed to identify whether multi-domain intervention targeting modifiable risk factors for dementia could prevent the progression of cognitive decline among older adults with type 2 diabetes mellitus (T2DM). This manuscript describes the study protocol for the J-MIND-Diabetes trial. Materials and Methods: Subjects of this trial will comprise a total of 300 T2DM outpatients aged 70-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the stratified permuted-block randomization methods. The intervention group will participate in multi-domain intervention programs aimed at: (1) management of metabolic and vascular risk factors; (2) physical exercise and self-monitoring of physical activity; (3) nutritional guidance; and (4) social participation. The control group will receive usual T2DM care and general instructions on dementia prevention. The primary and secondary outcomes will be assessed at baseline, at 6- and 18-month follow-up. The primary outcome is change from baseline at 18 months in a global composite score combining several neuropsychological domains, including global cognitive function, memory, attention, executive function, processing speed and language. Secondary outcomes include: (1) cognitive changes in neuropsychological tests; (2) changes in geriatrics assessments; (3) metabolic control and diabetic complications; (4) changes in blood and urinary markers. Discussion: This trial will be the first trial to demonstrate the effectiveness of multi-domain intervention in preventing cognitive decline in older adults with T2DM at increased risk of dementia in Japan. Trial Registration: UMIN000035911; Registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) 18 February 2019. (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000040908).

Rationale and design of an investigator-initiated, multicenter, prospective open-label, randomized trial to evaluate the effect of ipragliflozin on endothelial dysfunction in type 2 diabetes and chronic kidney disease: the PROCEED trial.

BACKGROUND: Type 2 diabetes (T2D) is associated with renal impairment and vascular endothelial dysfunction. Therefore, this pathological connection is an important therapeutic target. Recent cardiovascular and renal outcome trials demonstrated that sodium glucose cotransporter 2 inhibitors (SGLT2is) consistently reduced the risks of cardiovascular and renal events and mortality in patients with T2D and various other background risks including chronic kidney disease (CKD). However, the precise mechanisms by which SGLT2is accords these therapeutic benefits remain uncertain. It is also unknown whether these SGLT2is-associated benefits are associated with the amelioration of endothelial dysfunction in patients with T2D and CKD. METHODS: The PROCEED trial is an investigator-initiated, prospective, multicenter, open-label, randomized-controlled trial. The target sample size is 110 subjects. After they furnish informed consent and their endothelial dysfunction is confirmed from their decreased reactive hyperemia indices (RHI), eligible participants with T2D (HbA1c, 6.0-9.0%) and established CKD (30 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 60 and/or ≥ urine albumin-to-creatinine ratio 30 mg/g Cr) will be randomized (1:1) to receive either 50 mg ipragliflozin daily or continuation of background treatment (non-SGLT2i). The primary endpoint is the change in RHI from baseline after 24 weeks. To compare the treatment effects between groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for HbA1c (< 7.0% or ≥ 7.0%), age (< 70 y or ≥ 70 y), RHI (< 1.67 or ≥ 1.67), eGFR (< 45 mL/min/1.73 m2 or ≥ 45 mL/min/1.73 m2), and smoking status. Prespecified responder analyses will be also conducted to determine the proportions of patients with clinically meaningful changes in RHI at 24 weeks. DISCUSSION: PROCEED is the first trial to examine the effects of ipragliflozin on endothelial dysfunction in patients with T2D and CKD. This ongoing trial will establish whether endothelial dysfunction is a therapeutic target of SGLT2is in this population. It will also provide deep insights into the potential mechanisms by which SGLT2is reduced the risks of cardiovascular and renal events in recent outcome trials. Trial registration Unique Trial Number, jRCTs071190054 (https://jrct.niph.go.jp/en-latest-detail/jRCTs071190054).

Association of One-Leg Standing Time with Discontinuation of Injectable Medications During Hospitalization Among Patients with Type 2 Diabetes.

INTRODUCTION: Persons with type 2 diabetes (T2D) are known to experience impaired physical ability even at the early stages of the disease. However, less attention has been paid to increasing physical ability than to increasing physical activity in the treatment of T2D. The aim of this study was to assess whether improved physical ability parameters are associated with the discontinuation of injectable medications once glycemic targets have been achieved among inpatients with inadequately controlled T2D across a wide range of ages. METHODS: Forty-three patients with glycated hemoglobin levels of ≥ 7.5% (58 mmol/mol) aged between 19 and 82 years who received insulin, glucagon-like peptide-1 receptor agonists or both at admission were enrolled in the study. Muscle strength for knee extension, one-leg standing time with eyes open test(OLST), whole-body reaction time and maximal oxygen uptake were assessed as parameters of physical ability. RESULTS: At admission, patients who during hospitalization discontinued injectable medications (n = 29; Discontinued group) had a shorter duration of diabetes, lower fat mass and higher skeletal muscle mass and performed better on all of the physical ability test parameters than those who continued on injectable medications during hospitalization (n = 14; Continued group). At discharge, patients in the Discontinued group had achieved better glycemic control than those in the Continued group, as indicated by lower mean plasma glucose levels according to the 7-point profile. Stepwise logistic regression analysis that included those variables that were significantly different between the Continued group and the Discontinued group, with the aim to identify candidate(s) of explanatory variables, revealed that only OLST was significantly associated with the discontinuation of injectable medication. Patients with an OLST of ≥ 60 s were more likely to discontinue injectable medication than those with an OLST of < 60 s (odds ratio 18.9; 95% confidence interval 2.0-178.8; p = 0.011). CONCLUSIONS: Among inpatients with inadequately controlled T2D diabetes, longer OLST appear to be associated with discontinuing injectable medications during hospitalization. OLST could possibly be useful as a novel patient factor to consider in de-intensifying injectable medication.

Cutaneous microangiopathy in patients with type 2 diabetes: Impaired vascular endothelial growth factor expression and its correlation with neuropathy, retinopathy and nephropathy.

AIMS/INTRODUCTION: To examine the three-dimensional morphology and vascular endothelial growth factor (VEGF) expression of skin microvasculature in patients with type 2 diabetes in relation to neuropathy, retinopathy and nephropathy. MATERIALS AND METHODS: The present study enrolled 17 individuals with type 2 diabetes and 16 without. Skin sections were double-immunostained for type IV collagen and VEGF-A or protein gene product 9.5. Projected images from confocal microscopy served to quantify the occupancy rate of subepidermal type IV collagen-immunoreactive microvascular basement membrane area (OR-T4MBM), subepidermal VEGF-A-immunoreactive area and the VEGF/T4MBM ratio, as well as the protein gene product 9.5-immunoreactive intraepidermal nerve fiber density. Reduced intraepidermal nerve fiber density was applied for the diagnosis of neuropathy, fundic ophthalmoscopy and fluorescein angiography for retinopathy, and microalbuminuria or persistent proteinuria for nephropathy. RESULTS: A total of 12 patients with diabetes had neuropathy, 10 had retinopathy and eight had nephropathy. Regardless of the presence or absence of neuropathy, retinopathy or nephropathy, OR-T4MBM was significantly increased in patients with diabetes compared with individuals without diabetes. In contrast, VEGF/T4MBM ratio was significantly decreased in those with neuropathy and retinopathy, as well as in those with and without nephropathy, whereas a trend toward a decreased VEGF/T4MBM ratio was seen in patients without retinopathy, as compared with individuals without diabetes. CONCLUSIONS: The present study is the first report to show that cutaneous microangiopathy, as indicated by subepidermal microvascular proliferation and impaired VEGF expression, appears to occur before the development of overt clinical neuropathy, retinopathy or nephropathy in patients with type 2 diabetes.

Sleep disturbance as a clinical sign for severe hypogonadism: efficacy of testosterone replacement therapy on sleep disturbance among hypogonadal men without obstructive sleep apnea.

OBJECTIVE: The present subanalysis of the EARTH study investigates the effects of one year testosterone replacement therapy (TRT) on sleep disturbance among hypogonadal men without obstructive sleep apnea. METHODS: Sleep disturbance was defined as three or more points in question 4 of the aging males symptoms (AMS) questionnaire. All participants completed the AMS scale, International Prostatic Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) and Short Form 36 (SF-36) health survey at baseline and after 12 months. Sexual symptoms were also evaluated based on three AMS subscores (Q15, 16 and 17). RESULTS: We identified 100 patients with sleep disturbance, of whom 48 (24 each in the TRT and control groups) were ultimately included for analysis. All SF-36 categories , AMS scale, IPSS and SHIM score subdomains were significantly worse in patients with sleep disturbance than in those without disturbance. Statistically significant differences in sleep disturbance, erectile symptoms, sexual desire and some domains of the SF-36 were observed between the TRT and control groups after 12 months. CONCLUSION: Sleep disturbance may be one of the clinical signs for severe hypogonadism. Moreover, TRT improved sleep conditions, sexual function and quality of life among hypogonadal men with sleep disturbance.

The relationship of one-leg standing time with peripheral nerve function and clinical neuropathy in patients with type 2 diabetes.

OBJECTIVE: This study aimed at exploring physical fitness including postural stability in relation to peripheral nerve function and clinical neuropathy in patients with type 2 diabetes across a wide range of ages. METHODS: We analyzed data collected from 139 patients with type 2 diabetes aged between 19 and 81 years, which included the peripheral nerve conduction parameters and coefficient of variation for normal R-R intervals (CVRR) at rest and during deep breathing. The results of neurological examinations to diagnose probable and confirmed diabetic neuropathies based on the minimal criteria proposed by the Toronto diabetic neuropathy expert group and a battery of physical fitness tests including one-leg standing time with eyes open were also assessed. Multiple linear and logistic regressions were used to estimate the relationships of the physical fitness measures with the parameters of peripheral and cardiac autonomic nerve functions and clinical neuropathies, respectively. Receiver operating characteristic curves were generated to depict the relation between sensitivity and specificity of one-leg standing time for probable and confirmed neuropathies. RESULTS: After adjustment for age and other potential confounders, one-leg standing time correlated with peripheral and cardiac autonomic nerve functions as well as with probable and confirmed neuropathies. The one-leg standing time of 23 s was found to be 66 and 63% sensitive and 81 and 77% specific for diagnosing probable and confirmed neuropathies, respectively. CONCLUSIONS: Short one-leg standing time was associated with peripheral and cardiac autonomic nerve dysfunction and clinical neuropathy in patients with type 2 diabetes, independent of age.

Effects of testosterone replacement therapy on hypogonadal men with osteopenia or osteoporosis: a subanalysis of a prospective randomized controlled study in Japan (EARTH study).

OBJECTIVE: We investigated the effects of testosterone replacement therapy (TRT) on bone mineral density (BMD) among hypogonadal men with osteopenia/osteoporosis. METHODS: From our previous EARTH study population, 74 patients with a clinical diagnosis of osteopenia or osteoporosis and hypogonadism were included in this study, as the TRT (n = 35) and control (n = 34) groups. The TRT group was administered 250 mg of testosterone enanthate injection every 4 weeks for 12 months. The BMD, waist circumference, body mass index, body fat percentage, and muscle volume were measured at baseline and at 12 months. Blood biochemical data, including total cholesterol, triglycerides, HDL-cholesterol, hemoglobin A1c, and adiponectin values were also evaluated. RESULTS: At the 12-month visit, BMD significantly increased in both groups. However, comparisons on changes of parameter values from baseline to the 12-month visit between the TRT and control groups were significantly different in BMD (5.0 ± 5.0 vs. 3.0 ± 3.2; p = .0434) and in adiponectin value (-0.90 ± 3.33 vs. 0.10 ± 2.04; p = .0192). There were no significant changes in other parameters. CONCLUSIONS: TRT for 12 months could improve BMD with a decrease in adiponectin levels among hypogonadal men with osteopenia/osteoporosis.

Effects of long-term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study).

Androgen replacement therapy (ART) efficacy on late-onset hypogonadism (LOH) has been widely investigated in Western countries; however, it remains controversial whether ART can improve health and prolong active lifestyles. We prospectively assessed long-term ART effects on the physical and mental statuses of aging men with LOH in Japan. The primary endpoint was health-related quality of life assessed by questionnaires. Secondary endpoints included glycemic control, lipid parameters, blood pressure, waist circumference, body composition, muscular strength, International Prostate Symptom Scores (IPSS), International Index of Erectile Function-5 (IIEF-5) scores, and serum prostate-specific antigen levels. Of the 1637 eligible volunteers, 334 patients > 40 years with LOH were randomly assigned to either the ART (n = 169) or control groups (n = 165). Fifty-two weeks after the initial treatment, ART significantly affected the role physical subdomain of the short form-36 health survey (SF-36) scale (P = 0.0318). ART was also associated with significant decreases in waist circumstance (P = 0.002) and serum triglyceride (TG) (P = 0.013) and with significant increases in whole-body and leg muscle mass volumes (P = 0.071 and 0.0108, respectively), serum hemoglobin (P < 0.001), IPSS voiding subscore (P = 0.0418), and the second question on IIEF-5 (P = 0.0049). There was no significant difference between the groups in terms of severe adverse events. In conclusion, in patients with LOH, long-term ART exerted beneficial effects on Role Physical subdomain of the SF-36 scale, serum TG, waist circumstance, muscle mass volume, voiding subscore of IPSS, and the second question of IIEF-5. We hope our study will contribute to the future development of this area.

Clinical Utility of Skin Biopsy in Differentiating between Parkinson's Disease and Multiple System Atrophy.

Background. It is often difficult to differentiate Parkinson's disease (PD) from multiple system atrophy (MSA), especially in their early stages. Objectives. To examine the clinical utility of histopathological analysis of biopsied skin from the chest wall and/or leg in differentiating between the two diseases. Methods. Skin biopsies from the lower leg and/or anterior chest wall were obtained from 38 patients with idiopathic PD (26 treated with levodopa and 12 levodopa-naïve) and 13 age-matched patients with MSA. We sought aggregates of phosphorylated α-synuclein on cutaneous nerve fibers using double fluorescence immunohistochemistry and confocal microscopy and measured intraepidermal nerve fiber density (IENFD). Results. Phosphorylated α-synuclein aggregates were identified on cutaneous nerves in two patients with PD (5.3%) but in none of the patients with MSA, and IENFD was significantly lower in patients with PD when compared to those with MSA. There was no difference in IENFD between levodopa-treated and levodopa-naïve patients with PD. Conclusions. Our findings suggest that an assessment of IENFD in biopsied skin could be a useful means of differentiating between PD and MSA but that detection of α-synuclein aggregates on cutaneous nerves in the distal sites of the body is insufficiently sensitive.

Lower Urinary Tract Symptoms are Associated with Erectile Function and Psychological Symptoms in Men with Late-Onset Hypogonadism Syndrome.

OBJECTIVE: We assessed the factors significantly associated with lower urinary tract symptoms (LUTS) in men with late-onset hypogonadism (LOH) syndrome. METHODS: The study population consisted of 258 patients aged 40 years or older diagnosed with LOH syndrome. Each patient completed a questionnaire study, such as the International Index of Erectile Function (IIEF) 5, Aging Male Score (AMS), and International Prostate Symptom Score (IPSS). Body mass index (BMI), waist size, and muscle volume were measured in all patients, and blood biochemical data, including total cholesterol, triglyceride, hemoglobin A1c, and free testosterone (free T), were also collected. We analyzed the factors that have effect on IPSS. RESULTS: The mean age of the patients was 64.9 ± 8.7 years, and the mean free T value was 7.3 ± 2.2 pg/mL. The critical factors affecting IPSS were IIEF5 score, BMI, muscle volume, age, AMS, and free T-value (P < 0.05). Age showed the strongest significant positive correlation with IPSS (r = 0.321, P < 0.001). Each factor was controlled for age. IIEF5 score and AMS were independent factors affecting IPSS (r = -0.221 and 0.195, respectively, P < 0.05). IPSS showed an inverse correlation with IIEF5, and a positive correlation with AMS. LUTS also had a weak negative correlation with Free T-value but this was not significant (r = -0.121, P = 0.061). CONCLUSION: Lower urinary tract symptoms were significantly correlated with erectile function and psychological symptoms in men with LOH syndrome.

The impact of low-dose insulin on peripheral nerve insulin receptor signaling in streptozotocin-induced diabetic rats.

BACKGROUND: The precise mechanisms of the neuroprotective effects of insulin in streptozotocin (STZ)-induced diabetic animals remain unknown, but altered peripheral nerve insulin receptor signaling due to insulin deficiency might be one cause. METHODOLOGY AND PRINCIPAL FINDINGS: Diabetes was induced in 10-week-old, male Wistar rats by injecting them with STZ (45 mg/kg). They were assigned to one group that received half of an insulin implant (∼1 U/day; I-group, n = 11) or another that remained untreated (U-group, n = 10) for 6 weeks. The controls were age- and sex-matched, non-diabetic Wistar rats (C-group, n = 12). Low-dose insulin did not change haemoglobin A1c, which increased by 136% in the U-group compared with the C-group. Thermal hypoalgesia and mechanical hyperalgesia developed in the U-group, but not in the I-group. Sensory and motor nerve conduction velocities decreased in the U-group, whereas sensory nerve conduction velocity increased by 7% (p = 0.0351) in the I-group compared with the U-group. Western blots showed unaltered total insulin receptor (IR), but a 31% decrease and 3.1- and 4.0-fold increases in phosphorylated IR, p44, and p42 MAPK protein levels, respectively, in sciatic nerves from the U-group compared with the C-group. Phosphorylated p44/42 MAPK protein decreased to control levels in the I-group (p<0.0001). CONCLUSIONS AND SIGNIFICANCE: Low-dose insulin deactivated p44/42 MAPK and ameliorated peripheral sensory nerve dysfunction in rats with STZ-induced diabetes. These findings support the notion that insulin deficiency per se introduces impaired insulin receptor signaling in type 1 diabetic neuropathy.

An efficient method for the synthesis of phenacyl ester-protected dipeptides using neutral alumina-supported sodium carbonate 'Na2 CO3 /n-Al2 O3 '.

In the synthesis of dipeptides (Boc-AA(1)-AA(2)-OPac: AA(1) and AA(2) represent amino acids) protected by phenacyl (Pac) ester, amines and solid bases as the base for the conversion of the trifluoroacetic acid (TFA) salt of the amino component (TFA·H-AA(2)-OPac) into the corresponding free amino component (H-AA(2)-OPac) were examined. The synthesis of a dipeptide (Boc-Ala-Gly-OPac) using amines for the conversion afforded an unsatisfactory yield with by-products. On the other hand, the use of neutral alumina-supported Na(2) CO(3) (Na(2)CO(3) /n-Al(2)O(3)) as a solid base for the conversion provided the dipeptide in a quantitative yield without by-products. The application of Na(2)CO(3) /n-Al2 O3 to the synthesis of some dipeptides protected by Pac ester gave the desired peptides in excellent yields.

Aberrant methylation of the TDMR of the GTF2A1L promoter does not affect fertilisation rates via TESE in patients with hypospermatogenesis.

Increasing evidence shows a relationship between epigenetic regulation and male infertility. The GTF2A1L gene promoter contains the DNA methylation site of a tissue-specific differentially methylated region (TDMR). Eighty-six patients with non-obstructive azoospermia were assessed for the DNA methylation state of CpG islands in the GTF2A1L promoter using testicular genomic DNA. Based on histological criteria, 26 of the 86 patients had normal spermatogenesis (controls), 17 had hypospermatogenesis and 26 had a Sertoli cell-only phenotype or tubular sclerosis. GTF2A1L TDMR methylation was significantly lower in testes DNA from control samples than from hypospermatogenic samples (P=0.029). Patients with hypospermatogenesis were divided into two subgroups: high DNA methylation (HM, n=5) and low DNA methylation (LM, n=12). The GTF2A1L TDMR methylation rate differed significantly between the HM and LM groups (P=0.0019), and GTF2A1L expression was significantly higher among the LM than in the HM patients (P=0.023). High TDMR methylation was correlated with low GTF2A1L gene expression levels. Both groups demonstrated relatively good outcomes with respect to sperm retrieval, fertilisation, pregnancy and childbirth rates. We observed that aberrant GTF2A1L gene expression was not correlated with fertilisation rates. The testicular sperm extraction (TESE) technique may be used to overcome male infertility due to aberrant TDMR methylation.