Endogenous ligand recognition and structural transition of a human PTH receptor.

Endogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the parathyroid hormone receptor 1 (PTH1R) and activate the stimulatory G-protein (Gs) signaling pathway. Intriguingly, the two ligands have distinct signaling and physiological properties: PTH evokes prolonged Gs activation, whereas PTHrP evokes transient Gs activation with reduced bone-resorption effects. The distinct molecular actions are ascribed to the differences in ligand recognition and dissociation kinetics. Here, we report cryoelectron microscopic structures of six forms of the human PTH1R-Gs complex in the presence of PTH or PTHrP at resolutions of 2.8 -4.1 Å. A comparison of the PTH-bound and PTHrP-bound structures reveals distinct ligand-receptor interactions underlying the ligand affinity and selectivity. Furthermore, five distinct PTH-bound structures, combined with computational analyses, provide insights into the unique and complex process of ligand dissociation from the receptor and shed light on the distinct durations of signaling induced by PTH and PTHrP.

Class B1 GPCR activation by an intracellular agonist.

G protein-coupled receptors (GPCRs) generally accommodate specific ligands in the orthosteric-binding pockets. Ligand binding triggers a receptor allosteric conformational change that leads to the activation of intracellular transducers, G proteins and ß-arrestins. Because these signals often induce adverse effects, the selective activation mechanism for each transducer must be elucidated. Thus, many orthosteric-biased agonists have been developed, and intracellular-biased agonists have recently attracted broad interest. These agonists bind within the receptor intracellular cavity and preferentially tune the specific signalling pathway over other signalling pathways, without allosteric rearrangement of the receptor from the extracellular side1-3. However, only antagonist-bound structures are currently available1,4-6, and there is no evidence to support that biased agonist binding occurs within the intracellular cavity. This limits the comprehension of intracellular-biased agonism and potential drug development. Here we report the cryogenic electron microscopy structure of a complex of Gs and the human parathyroid hormone type 1 receptor (PTH1R) bound to a PTH1R agonist, PCO371. PCO371 binds within an intracellular pocket of PTH1R and directly interacts with Gs. The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation. PCO371 stabilizes the significantly outward-bent conformation of transmembrane helix 6, which facilitates binding to G proteins rather than ß-arrestins. Furthermore, PCO371 binds within the highly conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs. Our study identifies a new and conserved intracellular agonist-binding pocket and provides evidence of a biased signalling mechanism that targets the receptor-transducer interface.

Cryo-EM structure of the ß3-adrenergic receptor reveals the molecular basis of subtype selectivity.

The ß3-adrenergic receptor (ß3AR) is predominantly expressed in adipose tissue and urinary bladder and has emerged as an attractive drug target for the treatment of type 2 diabetes, obesity, and overactive bladder (OAB). Here, we report the cryogenic electron microscopy structure of the ß3AR-Gs signaling complex with the selective agonist mirabegron, a first-in-class drug for OAB. Comparison of this structure with the previously reported ß1AR and ß2AR structures reveals a receptor activation mechanism upon mirabegron binding to the orthosteric site. Notably, the narrower exosite in ß3AR creates a perpendicular pocket for mirabegron. Mutational analyses suggest that a combination of both the exosite shape and the amino-acid-residue substitutions defines the drug selectivity of the ßAR agonists. Our findings provide a molecular basis for ßAR subtype selectivity, allowing the design of more-selective agents with fewer adverse effects.

Thyroid hemiatrophy associated with papillary thyroid carcinoma.

PURPOSE: The present study aimed to investigate CT imaging features, pathological findings, and prognosis in patients with thyroid hemiatrophy (THA) associated with papillary thyroid carcinoma (PTC). METHODS: This retrospective study included 225 patients with histopathologically proven PTC treated by surgical resection who underwent preoperative CT scanning. On CT images, THA was defined as thyroid parenchymal hemiatrophy on the ipsilateral side of PTC. CT findings, overall survival, and disease-free survival were compared between patients with and without THA. Pathological findings were also assessed in PTCs with and without THA. RESULTS: THA was observed in 35 of 225 (16%) patients with PTC. Atrophic thyroid parenchyma was observed in the right lobe of 20 patients (57%) and in the left lobe of the remaining 15 patients (43%). With respect to the solid components within PTCs, contrast-enhanced CT attenuation (114.2 ± 18.2 vs. 126.7 ± 31.3 HU; p < 0.05) and CT attenuation change for contrast-enhanced CT minus unenhanced CT (60.2 ± 18.1 vs. 72.3 ± 31.0 HU; p < 0.05) were significantly lower in PTCs with THA than in those without THA. Histopathologically, almost all PTCs with THA (97%) had keloid-like collagen, which is broad bundles of hypocellular collagen with bright eosinophilic hyalinization, typically observed in keloid. However, no significant differences were observed in the prognosis between the two groups. CONCLUSION: THA was occasionally observed in patients with PTC. Weak contrast-enhancement was distinct characteristic of PTC patients with THA, which is probably caused by keloid-like collagen.

Efficacy of a new vacuum erection device (Vigor 2020) for erectile dysfunction: A retrospective study in Japan.

OBJECTIVES: The vacuum erection device (VED) is a second-line treatment tool recommended in erectile dysfunction (ED) guidelines but has long been unavailable in Japan. A new VED, Vigor 2020® (A & HB Company Limited, Tokyo, Japan), has now been manufactured and received medical approval from the Pharmaceuticals and Medical Devices Agency in Japan. We conducted a retrospective observational study of ED patients who used Vigor 2020 in clinical practice. METHODS: We analyzed male ED patients aged ≥20 years treated with Vigor 2020 in our outpatient clinics. The primary endpoint was improvement of erection as evaluated by an Erection Hardness Score (EHS) of ≥1 point. Secondary endpoints were improvement of sexual function and adverse events as evaluated by the International Index of Erectile Function (IIEF) and Male Sexual Health Questionnaire for assessing ejaculatory dysfunction (MSHQ-EjD). RESULTS: Thirty-three patients (mean age, 57.21 [27-86] years) could be evaluated before and after using Vigor 2020. Among the 16 patients with baseline EHS ≤2, 14 (93.33%) improved by ≥1 point, and 10 of these 16 patients (62.50%) improved to EHS ≥3 and could insert vaginally. Significant improvement was observed for IIEF total score and for the MSHQ-EjD in patients with an EHS of ≥3 after use of Vigor 2020. No patient experienced significant adverse events. CONCLUSIONS: The Vigor 2020 may be an efficacious treatment tool for ED. Patients with significant ED experienced not only significant improvement of erection but also improvement of ejaculation with its use.

Novel testosterone gel improves serum testosterone concentrations and aging males' symptoms in patients with late-onset hypogonadism: an active control equivalence, randomized, double-blind, crossover study.

Late-onset hypogonadism (LOH) is generally treated with testosterone replacement therapy. Intramuscular injection of testosterone enanthate is used for LOH in Japan but requires regular painful injections administered every 2-3 weeks at a clinic. Testosterone 2% (AndroForte 2® [AF2]) is available for treating LOH but is expensive because it is imported. We developed a new 2% testosterone gel (NTG) and hypothesized that in patients with LOH, NTG would improve serum testosterone concentrations and Aging Males' Symptoms (AMS) scores compared with AF2. We enrolled men with low levels of serum free testosterone (<11.8 pg/mL) and androgen deficiency symptoms (AMS score >27). The primary endpoint was equivalent change in serum testosterone concentrations with NTG compared to AF2. Secondary endpoints were equivalent change in AMS scores for each question with NTG compared to AF2. Each of AF2 or NTG was administered to the study subjects (23 men aged 42-71 years) for 4 weeks separated by a washout period of 2 weeks. The subjects were randomly divided into men who first received NTG and those who first received AF2. No subject experienced any adverse events throughout the study. Compared with the baseline values of serum testosterone, those following NTG and AF2 treatment were significantly higher and were also significantly higher in the subjects taking NTG versus AF2. NTG administration significantly improved the AMS score, whereas AF2 did not. This initial study has shown that this new NTG formulation may be effective in improving serum testosterone concentrations and also LOH-related symptoms.

Efficacy of testosterone replacement treatment for patients with symptoms of late-onset hypogonadism based on real-world patient satisfaction.

Late-onset hypogonadism is generally treated with testosterone replacement treatment. However, the efficacy rate of treatment for patients with low testosterone is not clear because patients without low testosterone are also treated in real-world clinical settings. This study comprised 110 men with low testosterone concentration of <3.0 ng/mL who underwent testosterone replacement treatment. Physical factors, laboratory and endocrinologic profiles, and scores of several questionnaires were assessed. Testosterone replacement treatment was performed with intramuscular injection of 250 mg of testosterone esters every 2-4 weeks, and efficacy was judged by patient satisfaction. After confirming efficacy, changes in several factors by the treatment were evaluated. Finally, the comparison between evaluation by patient satisfaction and by that with the questionnaires was assessed. Among the 110 patients, 77 (70.0%) were satisfied with the treatment, which was effective in 65.7%, 71.4%, and 73.1% of patients with mental, physical, and sexual dysfunction, respectively. The questionnaire scores including the Aging Males Symptoms rating scale were significantly improved in both the satisfaction and non-satisfaction group. However, no significant differences in the amount of change in questionnaire scores were found for all questionnaire scores improved by testosterone replacement treatment between the groups. Patient satisfaction was not associated with improvement of the Aging Males Symptoms score. Although testosterone replacement treatment was effective for 70.0% of the hypogonadal patients, patient satisfaction did not correlate with improvement of questionnaire scores. We concluded that not only questionnaire results but also patient satisfaction is important when evaluating efficacy in patients undergoing testosterone replacement treatment.

MRI features of subcutaneous anterior knee mass associated with a focal defect of the patellar retinaculum.

OBJECTIVE: The purpose of this study was to assess the frequency and MRI features of a subcutaneous anterior knee mass herniated from the infrapatellar fat pad (IPFP) through a focal defect of the patellar retinaculum (PR). MATERIALS AND METHODS: This study included 94 patients (44 men; age range, 1-80 years; mean age, 52 years) with clinically palpable subcutaneous anterior knee masses who underwent MRI between January 2007 and July 2022. Two radiologists retrospectively reviewed MRI findings of subcutaneous masses associated with a focal PR defect (location and size of the defect and characteristics of the mass). RESULTS: Among 94 patients, 15 (16%; 5 men; age range, 49-80 years; mean age, 67 years) had subcutaneous masses herniated from the IPFP through a focal PR defect. The defect was single (13/15, 87%) and more frequently observed in the lateral than in the medial (11/15, 73% vs. 4/15, 27%) PR. The defect occurred in the anterior segment (15/15, 100%) and was more frequently observed in the lower (10/15, 67%) than in the middle (5/15, 33%) and upper portions (0/15, 0%). The mean maximum length of the defect in axial and oblique planes was 14 mm and 25 mm, respectively. The defect-associated subcutaneous masses included lipomatous lesion (6/15, 40%), osteochondromatous lesion (5/16, 33%), and synovial fluid or ganglion cyst (4/15, 27%). CONCLUSION: Subcutaneous anterior knee masses were associated with a focal PR defect in 16% cases. The location of a focal PR defect was characterized by the lateral, anterior, and lower segments.

Efficacy and patient satisfaction of low-intensity shockwave treatment for erectile dysfunction in a retrospective real-world study in Japan.

OBJECTIVES: To clarify the efficacy of low-intensity extracorporeal shockwave therapy for patients with erectile dysfunction, compare the efficacy between two types of lithotripters (ED1000 [focused type] and Renova [linear type]), and detect factors indicative of therapeutic gain with the treatment. METHODS: This retrospective study included 76 patients (52.8 ± 11.7 years) treated by ED1000 (12 times over 9 weeks) and 484 patients (52.5 ± 11.6 years) treated by Renova (4 times over 4 weeks). Age, sexual symptoms scores, and blood examinations were assessed. Efficacy was judged by improvement of the scores and patient satisfaction and compared between patients at 1 month after treatment with the lithotripters. Independent factors influencing efficacy by Renova were also assessed. RESULTS: Sexual symptom scores were improved significantly by both lithotripters, although the changes in the scores did not differ significantly between them. Efficacy rate as judged by patient satisfaction was 65.8% with the ED1000 and 71.1% with Renova, also without significant difference. Among several factors including age, sexual symptoms scores, endocrinological factors, metabolic factors, and the rate of phosphodiesterase type 5 inhibitor use, only age was found to be an independent factor influencing the efficacy of Renova. CONCLUSION: We clearly showed the high efficacy of both lithotripters. Although the efficacy rate did not differ between them, we speculated that the fewer treatment sessions needed with the Renova versus the ED1000 would be a great advantage for patients. We also suggest that Renova should be recommended for patients younger than 70 years of age.

Low serum zinc concentration is associated with low serum testosterone but not erectile function.

OBJECTIVE: To investigate the relation between serum zinc concentration and several factors, including serum testosterone concentration and the score of questionnaires on sexual function in patients with sexual problems. METHODS: This study comprised 720 men (age, 46.3 [21-83] years) with some kind of sexual problem. Age, scores of the Sexual Health Inventory for Men and the Erection Hardness Score, and endocrinologic data including serum concentrations of testosterone, prostate-specific antigen, and zinc were included in this study. After serum zinc concentration of the men was classified into 5 groups (<70, 70≤ <80, 80≤ <90, 90≤ <100, ≤100 µg/dl), the relation of each parameter with serum zinc concentration was assessed for a trend analysis. Finally, the relation between serum concentrations of zinc and testosterone as well sexual function evaluated by the scores of the questionnaires was investigated. RESULTS: Only serum testosterone concentration (ptrend = 0.028) and serum cortisol concentration (ptrend = 0.003) showed a statistically significant relation to serum zinc concentration by trend analysis. Interestingly, trend analysis between serum concentrations of testosterone and zinc still showed a significant association after adjustment for serum cortisol concentration (ptrend = 0.032). However, no significant association was found in the relation between serum zinc concentration and the scores of the questionnaires after adjustment for serum concentrations of testosterone and cortisol. CONCLUSION: We clearly showed that after adjustment for serum cortisol concentration by trend analysis, serum testosterone concentration decreased as serum zinc concentration decreased, although sexual symptoms were not associated with this decrease.

Therapeutic efficacy and safety of a free-standing motorized ejaculation aid for patients with intravaginal ejaculatory dysfunction.

Purpose: There are no approved drugs or devices for the treatment of intravaginal ejaculation disorders, and treatment is often difficult. This study aimed to evaluate the efficacy and safety of the A10 Cyclone SA + PLUS® ejaculation aid (Rends Co., Ltd., Chiba, Japan), which allows the user to adjust the intensity of stimulation, for intravaginal ejaculation disorders. Methods: Each participant was instructed to perform practice masturbation with the A10 Cyclone SA + PLUS to simulate vaginal ejaculation. After 8 weeks of training, the participants were asked about their intravaginal ejaculation status. Sexual function was also evaluated before and after the training using several specific questionnaires, including the numerical rating scale for ejaculatory satisfaction. Results: Among the 10 participants (41.5 ± 3.21 years) who completed the training and questionnaire evaluation, four (40%) became capable of intravaginal ejaculation. The questionnaire evaluation showed predominant improvement after training in the ejaculation-capable group according to the numerical rating scale, which expresses satisfaction with ejaculation. The participants experienced no significant adverse events. Conclusion: As no effective treatment currently exists for intravaginal ejaculation disorders, we conclude that the A10 Cyclone SA + PLUS may be one treatment tool for intravaginal ejaculation disorders with good efficacy and no adverse events.

Cryo-EM structures of the ß3 adrenergic receptor bound to solabegron and isoproterenol.

The ß3-adrenergic receptor (ß3AR) is the most essential drug target for overactive bladder and has therapeutic potentials for the treatments of type 2 diabetes and obesity. Here, we report the cryo-electron microscopy structures of the ß3AR-Gs signaling complexes with the selective agonist, solabegron and the nonselective agonist, isoproterenol. Comparison of the isoproterenol-, mirabegron-, and solabegron-bound ß3AR structures revealed that the extracellular loop 2 changes its conformation depending on the bound agonist and plays an essential role in solabegron binding. Moreover, ß3AR has an intrinsically narrow exosite, regardless of the agonist type. This structural feature clearly explains why ß3AR prefers mirabegron and solabegron, as the narrow exosite is suitable for binding with agonists with elongated shapes. Our study deepens the understanding of the binding characteristics of ß3AR agonists and may pave the way for developing ß3AR-selective drugs.

Simultaneous Evaluation of Membrane Permeability and UDP-Glucuronosyltransferase-Mediated Metabolism of Food-Derived Compounds Using Human Induced Pluripotent Stem Cell-Derived Small Intestinal Epithelial Cells.

Pharmacokinetic prediction after oral ingestion is important for quantitative risk assessment of food-derived compounds. To evaluate the utility of human intestinal absorption prediction, we compared the membrane permeability and metabolic activities of human induced pluripotent stem cell-derived small intestinal epithelial cells (hiPSC-SIECs) with Caco-2 cells or human primary enterocytes (hPECs). We found that membrane permeability in hiPSC-SIECs had better predictivity than that in Caco-2 cells against 21 drugs with known human intestinal availability (r = 0.830 and 0.401, respectively). Membrane permeability in hiPSC-SIECs was only 0.019-0.25-fold as compared with that in Caco-2 cells for 7 in 15 food-derived compounds, primarily those that were reported to undergo glucuronidation metabolism. The metabolic rates of the glucuronide conjugate were similar or higher in hiPSC-SIECs as compared with hPECs but lower in Caco-2 cells. Expression levels of UDP-glucuronosyltransferase (UGT) isoform mRNA in hiPSC-SIECs were similar or higher as compared with hPECs. Therefore, hiPSC-SIECs could be a useful tool for predicting human intestinal absorption to simultaneously evaluate membrane permeability and UGT-mediated metabolism. SIGNIFICANCE STATEMENT: Gastrointestinal absorption is an important step for predicting the internal exposure of food-derived compounds. This research revealed that human induced pluripotent stem cell-derived small intestinal cells (hiPSC-SIECs) had better predictivity of intestinal availability than Caco-2 cells; furthermore, the metabolic rates of UDP-glucuronosyltransferase (UGT) substrates of hiPSC-SIECs were closer to those of human primary enterocytes than those of Caco-2 cells. Therefore, hiPSC-SIECs could be a useful tool for predicting human intestinal absorption to simultaneously evaluate membrane permeability and UGT-mediated metabolism.

Comparative whole transcriptome analysis of Parkinson's disease focusing on the efficacy of zonisamide.

OBJECTIVE: Interindividual variations in responsiveness to zonisamide in patients with Parkinson's disease (PD) have been observed in clinical settings. To decipher the molecular mechanisms determining the efficacy of zonisamide, we conducted whole transcriptome sequencing analysis of patients with PD. METHODS: We selected 23 super-responders (SRs) and 25 non-responders (NRs) to zonisamide from patients with PD who had participated in a previous clinical trial for the approval of zonisamide for the treatment of 'wearing-off'. Whole transcriptome analysis of peripheral blood was conducted on samples taken before and 12 weeks after zonisamide treatment. We performed differential gene expression analysis to compare between the SRs and NRs at each time point. RESULTS: Differentially expressed genes in the pre-treatment samples were significantly enriched for glutamatergic synapses and insulin-like growth factor binding (Padj=7.8 × 10-3 and 0.029, respectively). The gene sets associated with these functions changed more dynamically by treatment in SRs than NRs (p=7.2 × 10-3 and 8.2 × 10-3, respectively). CONCLUSIONS: Our results suggest that the efficacy of zonisamide in PD patients is associated with glutamate-related synaptic modulation and p53-mediated dopaminergic neural loss. Their transcriptomic differences could be captured before treatment, which would lead to the realisation of future personalised treatment.

MRI findings to differentiate musculoskeletal dedifferentiated liposarcoma from atypical lipomatous tumor.

OBJECTIVE: This study aimed to assess the efficacy of using MRI findings for differentiating musculoskeletal dedifferentiated liposarcoma (DDLP) from atypical lipomatous tumor (ALT). MATERIALS AND METHODS: This study included 22 patients with histopathologically proven DDLP and 35 with ALT in the musculoskeletal areas. All DDLPs were immunohistochemically positive for MDM2. MRI findings for both pathologies were retrospectively reviewed and compared. RESULTS: The maximum lesion diameter was significantly lower in DDLPs than in ALTs (p < 0.01). Ill-defined margin, peritumoral edema, and tail sign were more frequently observed in DDLPs than in ALTs (p < 0.01, respectively). The fatty component was less frequently observed in DDLPs than in ALTs (27 vs. 100%; p < 0.01), whereas the non-fatty component was more frequently observed in DDLPs than in ALTs (100 vs. 11%; p < 0.01). The occupation rate by non-fatty components was significantly higher in DDLPs than in ALTs (p < 0.01). No significant differences were observed in imaging findings associated with fatty component; however, necrosis within the non-fatty component on the contrast-enhanced image was more frequently observed in DDLPs than in ALTs (72 vs. 0%, p < 0.05). CONCLUSION: DDLPs always had a non-fatty component, whereas ALTs always had fatty component. Ill-defined margin, peritumoral edema, tail sign, and necrosis within non-fatty components were useful MRI features for differentiating musculoskeletal DDLP from ALT.

Galectin 3-binding protein suppresses amyloid-ß production by modulating ß-cleavage of amyloid precursor protein.

Alzheimer's disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of ß-amyloid (Aß) peptides. Aß is produced from amyloid precursor protein (APP) that is sequentially cleaved by ß- and γ-secretases. Therefore, APP processing has been a target in therapeutic strategies for managing AD; however, no effective treatment of AD patients is currently available. Here, to identify endogenous factors that modulate Aß production, we performed a gene microarray-based transcriptome analysis of neuronal cells derived from human induced pluripotent stem cells, because Aß production in these cells changes during neuronal differentiation. We found that expression of the glycophosphatidylinositol-specific phospholipase D1 (GPLD1) gene is associated with these changes in Aß production. GPLD1 overexpression in HEK293 cells increased the secretion of galectin 3-binding protein (GAL3BP), which suppressed Aß production in an AD model, neuroglioma H4 cells. Mechanistically, GAL3BP suppressed Aß production by directly interacting with APP and thereby inhibiting APP processing by ß-secretase. Furthermore, we show that cells take up extracellularly added GAL3BP via endocytosis and that GAL3BP is localized in close proximity to APP in endosomes where amyloidogenic APP processing takes place. Taken together, our results indicate that GAL3BP may be a suitable target of AD-modifying drugs in future therapeutic strategies for managing AD.

Genetic variations and clinical spectrum of dystroglycanopathy in a large cohort of Chinese patients.

Dystroglycanopathy is a group of muscular dystrophies with deficient glycosylation of alpha-dystroglycan (α-DG). We recruited patients from 36 tertiary academic hospitals in China. In total, 143 patients with genetically diagnosed dystroglycanopathy were enrolled. Of these, limb girdle muscular dystrophy was the most common initial diagnosis (83 patients) and Walker-Warburg syndrome was the least common (1 patient). In 143 patients, mutations in FKRP gene were the most prevalent (62 patients), followed by POMT2, POMT1 (16), POMGNT1, ISPD (14), FKTN, GMPPB, B3GALNT2, DPM3, and DAG1. Several frequent mutations were identified in FKRP, POMT1, POMGNT1, ISPD, and FKTN genes. Many of these were founder mutations. Patients with FKRP mutations tended to have milder phenotypes, while those with mutations in POMGNT1 genes had more severe phenotypes. Mental retardation was a clinical feature associated with mutations of POMT1 gene. Detailed clinical data of 83 patients followed up in Peking University First Hospital were further analyzed. Our clinical and genetic analysis of a large cohort of Chinese patients with dystroglycanopathy expanded the genotype variation and clinical spectrum of congenital muscular dystrophies.

Quantitative analysis of the anatomical changes in the scalp and hair follicles in androgenetic alopecia using magnetic resonance imaging.

BACKGROUND: Although the structural changes of the scalp in androgenetic alopecia (AGA) have been reported, these changes have been poorly understood. It is expected that modern MRI would visualize the scalp anatomy in vivo. This study aimed to explore whether AGA causes (a) changes in the thickness of the scalp, (b) anatomical changes in the hair follicles, and (c) changes in the signal intensity of MRI. MATERIALS AND METHODS: Twenty-seven volunteers underwent MRI for hair and scalp (MRH) and were categorized into two according to the Hamilton-Norwood Scale: the "AGA group" and the "normal group." Two radiologists analyzed the thickness and signal intensity of the scalp, and the depth of hair follicles. These measurements were compared between the two groups. RESULTS: The thickness of the hypodermis and the entire scalp was significantly thinner in the AGA group than in the control group. The AGA group had significantly shallower depth of hair follicles and relative depth of the hair follicles to that of the entire scalp than the normal group. The hypodermis showed higher signal intensity in the AGA group than the normal group. CONCLUSION: MRH allowed noninvasive visualization of the scalp anatomy and demonstrated the thinner nature of the entire scalp and hypodermis, along with the shallower depth of the hair follicles in the AGA group in comparison to the normal group. Additionally, MRH demonstrated the increased MR signal intensity in the scalp associated with AGA. MRH may be a promising new method for quantitative and objective analyses of AGA.

Relationship between serum zinc concentration and semen quality in newly-wed men.

OBJECTIVES: To clarify factors associated with semen quality and confirm whether there is an association between semen quality and serum zinc concentration. METHODS: A semen test was performed on 217 men just after or just before marriage. Variables assessed in the study were: age; symptomatic scores, including sexual function evaluated using several specific questionnaires; endocrinological profiles, especially follicle-stimulating hormone; and serum zinc concentrations. Based on World Health Organization criteria for assessing sperm quality, semen volume ≥1.5 mL, sperm concentration ≥15 million/mL, or sperm motility rate ≥40%, the men were grouped according to whether they had values below or above these criteria. The two groups were compared with regard to the study variables, and correlation between serum zinc concentration and semen quality was evaluated. Independent predictors for inclusion in the group with values below the criteria were investigated further. RESULTS: Of the 217 men included in the study, 45 (20.7%) were categorized as having values below the World Health Organization criteria. The men in this group were significantly older and had significantly worse sexual function, significantly higher follicle-stimulating hormone levels, and significantly lower serum zinc concentrations, than those in the group with values above the criteria. There was no significant correlation between serum zinc concentration and semen quality. However, the independent predictors for having values below the criteria in binomial logistic regression analysis were follicle-stimulating hormone and serum zinc concentration. CONCLUSION: We suggest that semen analysis may be considered in men with a low level of serum zinc and high level of follicle-stimulating hormone when developing a life plan for fertilization.

Temporal requirement of dystroglycan glycosylation during brain development and rescue of severe cortical dysplasia via gene delivery in the fetal stage.

Congenital muscular dystrophies (CMDs) are characterized by progressive weakness and degeneration of skeletal muscle. In several forms of CMD, abnormal glycosylation of α-dystroglycan (α-DG) results in conditions collectively known as dystroglycanopathies, which are associated with central nervous system involvement. We recently demonstrated that fukutin, the gene responsible for Fukuyama congenital muscular dystrophy, encodes the ribitol-phosphate transferase essential for dystroglycan function. Brain pathology in patients with dystroglycanopathy typically includes cobblestone lissencephaly, mental retardation, and refractory epilepsy; however, some patients exhibit average intelligence, with few or almost no structural defects. Currently, there is no effective treatment for dystroglycanopathy, and the mechanisms underlying the generation of this broad clinical spectrum remain unknown. Here, we analysed four distinct mouse models of dystroglycanopathy: two brain-selective fukutin conditional knockout strains (neuronal stem cell-selective Nestin-fukutin-cKO and forebrain-selective Emx1-fukutin-cKO), a FukutinHp strain with the founder retrotransposal insertion in the fukutin gene, and a spontaneous Large-mutant Largemyd strain. These models exhibit variations in the severity of brain pathology, replicating the clinical heterogeneity of dystroglycanopathy. Immunofluorescence analysis of the developing cortex suggested that residual glycosylation of α-DG at embryonic day 13.5 (E13.5), when cortical dysplasia is not yet apparent, may contribute to subsequent phenotypic heterogeneity. Surprisingly, delivery of fukutin or Large into the brains of mice at E12.5 prevented severe brain malformation in Emx1-fukutin-cKO and Largemyd/myd mice, respectively. These findings indicate that spatiotemporal persistence of functionally glycosylated α-DG may be crucial for brain development and modulation of glycosylation during the fetal stage could be a potential therapeutic strategy for dystroglycanopathy.