Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a “one-size-fits-all” approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Bilateral Implantation of Centromedian‐Parafascicularis Complex and GPi: A New Combination of Unconventional Targets for Deep Brain Stimulation in Severe Parkinson Disease

Objectives. Traditional deep brain stimulation (DBS) at the subthalamic nucleus (STN) has proved to be efficacious on core Parkinsonian symptoms. However, very disabling l ‐dopa–induced abnormal involuntary movements (AIMs) and axial signs are slightly affected, suggesting that we target less conventional targets. Our candidates for DBS were the globus pallidus internus (GPi) plus the intralaminar thalamic complex (Pf or CM), given its extensive functional links with basal ganglia nuclei. Materials and Methods. The routine utilization of our innovative stereotactic apparatus allows us to implant, at the same time, both the CM‐Pf complex together with the GPi in six Parkinson disease patients. Both intraoperative and postoperative neurophysiologic assessments helped us recognize functional subregions while optimizing implantation of electrodes. Unified Parkinson disease rating scale (UPDRS) motor scores, AIMs, and freezing were carefully blindly evaluated for each condition. Results. A significant amelioration of UPDRS scores was achieved by simultaneous activation of both targets. CM‐Pf activation was only slightly effective in reducing rigidity and akinesia, but more efficacious on freezing. Not surprisingly, AIMs were peculiarly decreased by the activation of the permanent electro‐catheter in the posteroventral GPi. Conclusions. These findings confirm that, in selected patients, it is conceivable to target structures other than the conventional STN in order to maximize clinical benefit.     

Gonadotropin-releasing hormone antagonists increase follicular fluid insulin-like growth factor-I and vascular endothelial growth factor during ovarian stimulation cycles.

The aim of the present study was to investigate the effect of gonadotropin-releasing hormone (GnRH) antagonists (GnRH-ant) on follicular fluid (FF) insulin-like growth factor-I (IGF-I) and FF vascular endothelial growth factor (VEGF) levels. Sixty women undergoing assisted reproduction were randomized and assigned to two different GnRH analog regimens: GnRH agonist (GnRH-a) and GnRH-ant. FF VEGF and FF IGF-I concentrations were significantly increased in the patients treated with GnRH-ant (p < 0.001). In the same patients we observed a statistically significant reduction in serum luteinizing hormone (LH) and estradiol (E2) levels (p < 0.001 and p < 0.05, respectively), FF E2 and FF androstenedione levels (p < 0.05 and p < 0.001, respectively), as well as a reduction in the number of pregnancies although this was not statistically significant. In the GnRH-ant group, FF VEGF levels were positively correlated with FF IGF-I levels, and both were negatively correlated with serum LH levels. The increase in FF IGF-I and FF VEGF levels in women treated with GnRH-ant could be explained by a deleterious follicular environment in response to profound suppression of LH and E2 levels.     

Histology as a prognostic factor in early gastric cancer.

Of 431 patients with gastric cancer observed in our institution, 23 (5.3%) had early gastric cancer (EGC). Macroscopic presentation, histology, depth of invasion, and lymph node involvement were evaluated in all the cases. All patients underwent surgery and an intensive follow-up was performed. Five of the 23 patients progressed, and the risk factors were examined. Histology seemed to be the main prognostic factor in our study, since intestinal type of EGC was associated to a significantly better prognosis. Total gastrectomy is indicated in the proximal localization of EGC, and should perhaps be performed also in cases presenting undifferentiated histology.     

A case of unilateral opercular syndrome associated with a subcortical lesion

Summary A patient who developed a unilateral opercular syndrome following a cerebrovascular accident is described. Computed tomography showed that the lesion did not affect the opercular cortex, but involved deep white matter and the head of the caudate nucleus of the left hemisphere. Persistent hypophonia and transient aphasia were associated. Comparison with previous cases is discussed.     

Dermoscopic Evolution of a Congenital Combined Nevus in Childhood

Background. A combined nevus most commonly consists of a blue nevus in combination with a Clark or Spitz nevus. Dermoscopically, combined nevus can mimic melanoma owing to the presence of dermoscopic features common to both types of lesions. Benign clinical and dermoscopic changes can occur in nevi over time, especially in children and young adults.
Objective. To describe the dermoscopic evolution of a congenital combined nevus showing unusual dermoscopic features.
Methods. Digital dermoscopic analysis was performed at the initial visit and after 8 months. The lesion was surgically excised and histopathologically examined.
Results. An asymptomatic plaque with a central blue area and peripheral brown pigmentation located on the back of a 13-year-old boy was diagnosed dermoscopically as combined nevus. Dermoscopic analysis 8 months later showed color changes from steel blue to gray-blue and black in the central area of the lesion, an increased number of blue-black dots or globules, and peripheral irregular streaks. Histopathology revealed typical features of a congenital combined nevus (blue nevus + compound nevus).
Conclusion. Over time, congenital combined nevus may show clinical and dermoscopic changes in size, color, and structure. Surgical excision is recommended when clinical and dermoscopic features are equivocal and the diagnosis of melanoma cannot be ruled out.
ANGELA FERRARI, MD, GIAN PIERO LOZZI, MD, MARIA CONCETTA FARGNOLI, MD, AND KETTY PERIS, MD, HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS.     

Correlation between amount of retinal afferents to the pretectal nucleus of the optic tract and dorsal terminal accessory optic nucleus and performance of horizontal optokinetic reflex in rat.

Intraocular kainic acid injection in Long-Evans rats induces loss of retinal afferents to subcortical visual centers as assessed by the axoplasmic transport of [14C]valine. The optical terminal fields of the pretectal nucleus of the optic tract (NOT), superior colliculus and accessory optic system (AOS) nuclei appear particularly affected. Since NOT and the AOS dorsal terminal nucleus (DTN) represent the first relay station of the visuomotor pathway mediating horizontal optokinetic nystagmus (HOKR), we have studied the characteristics of HOKR after various degrees of retinal deafferentation of these nuclei induced by intraocular KA injection. Taking advantage of the arrangement of the primary optic projections to NOT-DTN, that in rats are almost entirely crossed, in each animal, monocular HOKR induced by stimulation of the injected eye was compared to monocular HOKR elicited by stimulation of the intact, ipsilateral eye. Following NOT-DTN optic denervation, HOKR gain always worsened, and in a way, that the greater the deficits of retinal afferents, the greater the HOKR inability to compensate for visual motion. Furthermore, for any given retinal denervation the higher the stimulus velocity, the greater the HOKR deficit. While the correlation between HOKR gain and the amount of retinal afferents to NOT-DTN would seem to indicate a functional homogeneity of the retinal ganglion cells sending axons to these nuclei, the finding that the extent of HOKR impairment also varied with velocity might not support the above view.