Automated chronic wounds medical assessment and tracking framework based on deep learning.

Chronic wounds are a latent health problem worldwide, due to high incidence of diseases such as diabetes and Hansen. Typically, wound evolution is tracked by medical staff through visual inspection, which becomes problematic for patients in rural areas with poor transportation and medical infrastructure. Alternatively, the design of software platforms for medical imaging applications has been increasingly prioritized. This work presents a framework for chronic wound tracking based on deep learning, which works on RGB images captured with smartphones, avoiding bulky and complicated acquisition setups. The framework integrates mainstream algorithms for medical image processing, including wound detection, segmentation, as well as quantitative analysis of area and perimeter. Additionally, a new chronic wounds dataset from leprosy patients is provided to the scientific community. Conducted experiments demonstrate the validity and accuracy of the proposed framework, with up to 84.5% in precision.

T-Regulatory Cells in Erythema Nodosum Leprosum: An Immunohistochemical and Image Morphometric Study.

ABSTRACT: Erythema nodosum leprosum (ENL) occurs as an immune-inflammatory complication of multibacillary leprosy (MBL), precipitated by an interaction between the host, bacilli, and the environment. This complication often causes significant morbidity due to systemic involvement and needs to be treated aggressively. T-regulatory cells (T-regs) are the immunomodulatory subset of T cells that are hypothesized to play a role in ENL. We have performed immunohistochemistry for FoxP3 (T-reg), CD3 (pan-T), CD4 (helper T), and CD8 (cytotoxic T) on 50 biopsy-proven cases of ENL along with 84 biopsy-proven cases of paucibacillary leprosy (PBL) (n = 49) and MBL (n = 35). Image morphometry was applied to objectively assess the relative preponderance of these subsets of T cells. The area fraction of T-regs showed a trend of reduction from PBL to MBL to ENL (P = 0.068), whereas the FoxP3:CD3 (T-reg: pan-T) ratio showed a significant reduction across these groups (P = 0.023). However, there was no significant difference of T-regs or FoxP3:CD3 ratio between MBL and ENL. The T-regs showed a significant positive correlation (P = 0.007) with the cytotoxic T cells in the skin biopsy. The presence of dermal eosinophils in ENL showed a trend association with the FoxP3:CD3 ratio (P = 0.05). Various histopathological parameters including epidermal spongiosis, dermal stromal edema, dermal ill-formed granuloma, and the presence of bacilli within the endothelium and vascular smooth muscle correlated with various T-cell subsets. Our study, one of the largest on this topic, objectively assessed the role of T-regs in the spectrum of leprosy. Nevertheless, the precipitation of ENL from MBL is probably not associated with the T-reg subset alone.

Reading of the Mitsuda test: comparison between diameter and total area by means of a computerized method.

The Mitsuda test is a skin test based on the individual's immune response through late and highly specific hypersensitivity reaction to the Mycobacterium leprae bacillus. A negative reaction identifies individuals who present a higher risk of becoming ill if exposed to M. leprae and, if they become ill, to develop the virchowian form of disease. The Mitsuda test reading is performed by means of a millimeter ruler. The dermatoscopy is a method that has not been used in the evaluation of cutaneous tests, although its use has increased in several areas. The study aimed to compare the results between the standardized reading and the total area of the Mitsuda test obtained by a computerized method which was structured by the association of digital dermatoscopy, the Dermatology Web system and the Image Tool 3.0 software. Data collection was performed at the Dermatology Outpatient Clinic of the Eduardo de Menezes Hospital, in Belo Horizonte, from November 2015 to August 2016. The sample consisted of 100 leprosy domiciliary contacts. There was an excellent agreement between the Mitsuda test (diameter and area), with a coefficient greater than 80%, and an excellent correlation with the Spearman's correlation coefficient (0.936). The intraclass correlation coefficient indicated a low (0.219) but significant agreement between the two measurements. In conclusion, there is a significant correlation between the standardized reading and the total area of the Mitsuda test. Digital dermoscopy can be an alternative instrument of evaluation, allowing the computerization and recording of the Mitsuda test.

Digital volumetric measurement of cutaneous leishmaniasis lesions: Blur estimation method.

BACKGROUND: Cutaneous leishmaniasis is a common parasitic infestation in Iran. With recent advantages in digital imaging, we have devised a novel non-contact objective method of measuring lesions. AIM: The aim of the study was to design a software system that analyzes images of cutaneous leishmaniasis lesions, objectively assess and monitor volume. METHODS: A photographic technique along with an image processing algorithm was applied to extract a three-dimensional map of the lesion from a simple two-dimensional picture. This method recovers depth on the basis of blur estimation. A macro lens with a low depth of field was used to blur the objects out of focus. To assess and compare the results, a polymer mold of the corresponding lesion was made and filled with liquid. The volume of liquid corresponded to the volume of the lesion. A total of thirty-seven patients were enrolled, and 48 lesions were analyzed. RESULTS: The mean volume measured by image processing was 159 µl (range: 8-685 µl), in comparison to an average of 170 µl (range: 6-800 µl) obtained from the molds. This was not significantly different. Statistical analysis by the Pearson correlation test showed a 'very good fit' correlation between these measured volumes (P < 0.001, r = 0.938). LIMITATION: The location and height of lesions were two important limitations in implementing this technique. If the lesion location is in the curvature region of body or the lesion height is less than 1 mm or more than 1 cm, this method will lose precision and accuracy. CONCLUSION: Image processing with blur estimation technique is an accurate and precise method to measure the volume of lesions in cutaneous leishmaniasis.

Immunohistochemical assessment of cell populations in leprosy-spectrum lesions and reactional forms.

In situ immunophenotyping of leprosy lesions can improve our understanding of the biology of inflammatory cells during the immune response to Mycobacterium leprae antigens. In the present study, biopsies from 10 healthy controls and 70 leprosy patients were selected, 10 for each of the following conditions: clinical tuberculoid (TT), borderline tuberculoid (BT), borderline borderline (BB), borderline lepromatous (BL), lepromatous (LL), reversal reaction (R1), and erythema nodosum leprosum (R2). Qualitative and quantitative immunohistochemical analyses were performed to detect CD3, CD4, CD8, FoxP3, CD20, CD138, CD1a, CD57, CD15, CD117, CD68, and CD163. In addition, histochemistry was employed to identify eosinophils. The amount of CD3+ and CD4+ T cells was higher in TT than in LL patients. CD8+ T cells were predominant in T lymphocyte infiltrations in the basal layer of the epidermis. The number of FoxP3+ cells was similar among different forms of the disease, but was higher in BL and LL than in R2 individuals. CD20+ lymphocytes were most abundant in TT samples, while CD138+ plasma cells displayed no detectable differences. Epithelioid macrophages from the center of TT and R1 granulomas exhibited the M1 phenotype (CD68+CD163-), whereas those in LL granulomas showed the M2 phenotype (CD68+CD163+). There was a gradual decrease in the amount of CD1a+ cells from the TT towards the LL form of the disease. A significant increase in the number of neutrophils was observed only in R2 samples. All the cells investigated, except eosinophils, participated in the immunopathogenesis of leprosy.

Immunohistochemical assessment of cell populations in leprosy-spectrum lesions and reactional forms

In situ immunophenotyping of leprosy lesions can improve our understanding of the biology of inflammatory cells during the immune response to Mycobacterium leprae antigens. In the present study, biopsies from 10 healthy controls and 70 leprosy patients were selected, 10 for each of the following conditions clinical tuberculoid (TT), borderline tuberculoid (BT), borderline borderline (BB), borderline lepromatous (BL), lepromatous (LL), reversal reaction (R1), and erythema nodosum leprosum (R2). Qualitative and quantitative immunohistochemical analyses were performed to detect CD3, CD4, CD8, FoxP3, CD20, CD138, CD1a, CD57, CD15, CD117, CD68, and CD163. In addition, histochemistry was employed to identify eosinophils. The amount of CD3+ and CD4+ T cells was higher in TT than in LL patients. CD8+ T cells were predominant in T lymphocyte infiltrations in the basal layer of the epidermis. The number of FoxP3+ cells was similar among different forms of the disease, but was higher in BL and LL than in R2 individuals. CD20+ lymphocytes were most abundant in TT samples, while CD138+ plasma cells displayed no detectable differences. Epithelioid macrophages from the center of TT and R1 granulomas exhibited the M1 phenotype (CD68+CD163-), whereas those in LL granulomas showed the M2 phenotype (CD68+CD163+). There was a gradual decrease in the amount of CD1a+ cells from the TT towards the LL form of the disease. A significant increase in the number of neutrophils was observed only in R2 samples. All the cells investigated, except eosinophils, participated in the immunopathogenesis of leprosy.

Impact of arterial input function selection on the accuracy of dynamic contrast-enhanced MRI quantitative analysis for the diagnosis of clinically significant prostate cancer.

PURPOSE: Using a limited temporal resolution dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) dataset to assess the impact of the arterial input function (AIF) choice on the transfer constant (K(trans) ) to distinguish prostate carcinoma (PCa) from benign tissue. MATERIALS AND METHODS: Thirty-eight patients with clinically important peripheral PCa (≥0.5 cc) were retrospectively studied. These patients underwent 1.5T multiparametric prostate MR with PCa and benign regions of interest (ROIs) selected using a visual registration with morphometric reconstruction obtained from radical prostatectomy. Using three pharmacokinetic (PK) analysis software programs, the mean K(trans) of ROIs was computed using three AIFs: an individual AIF (Ind-AIF) and two literature population average AIFs of Weinmann (W-AIF) and of Fritz-Hansen (FH-AIF). A pairwise comparison of the area under the receiver operating characteristic curves (AUROCC) obtained with different AIFs was performed. RESULTS: AUROCCs obtained with W-AIF (ranging from 0.801 to 0.843) were significantly higher than FH-AIF (ranging from 0.698 to 0.780, 0.002 ≤ P ≤ 0.045) and similar to or higher than Ind-AIF (ranging from 0.591 to 0.839, 0.014 ≤ P ≤ 0.9). Ind-AIF and FH-AIF provided similar AUROCC (0.34 ≤ P ≤ 0.81). The pairwise correlation of K(trans) values was moderate to very strong when comparing W-AIF with FH-AIF (the Spearman's correlation coefficients [SCCs] ranged from 0.55 to 0.93) and very weak to moderate when comparing W-AIF with Ind-AIF (the SCCs ranged from 0.018 to 0.59) or FH-AIF with Ind-AIF (the SCCs ranged from 0.30 to 0.51). CONCLUSION: W-AIF yielded a higher performance than FH-AIF and a similar or higher performance than Ind-AIF in distinguishing PCa from benign tissue.

Are human peripheral nerves sensitive to X-ray imaging?

Diagnostic imaging techniques play an important role in assessing the exact location, cause, and extent of a nerve lesion, thus allowing clinicians to diagnose and manage more effectively a variety of pathological conditions, such as entrapment syndromes, traumatic injuries, and space-occupying lesions. Ultrasound and nuclear magnetic resonance imaging are becoming useful methods for this purpose, but they still lack spatial resolution. In this regard, recent phase contrast x-ray imaging experiments of peripheral nerve allowed the visualization of each nerve fiber surrounded by its myelin sheath as clearly as optical microscopy. In the present study, we attempted to produce high-resolution x-ray phase contrast images of a human sciatic nerve by using synchrotron radiation propagation-based imaging. The images showed high contrast and high spatial resolution, allowing clear identification of each fascicle structure and surrounding connective tissue. The outstanding result is the detection of such structures by phase contrast x-ray tomography of a thick human sciatic nerve section. This may further enable the identification of diverse pathological patterns, such as Wallerian degeneration, hypertrophic neuropathy, inflammatory infiltration, leprosy neuropathy and amyloid deposits. To the best of our knowledge, this is the first successful phase contrast x-ray imaging experiment of a human peripheral nerve sample. Our long-term goal is to develop peripheral nerve imaging methods that could supersede biopsy procedures.

Retrospectively gated cardiac cine imaging with temporal and spatial acceleration.

Parallel imaging methods are routinely used to accelerate the image acquisition process in cardiac cine imaging. The addition of a temporal acceleration method, whereby k-space is sampled differently for different time frames, has been shown in prior work to improve image quality as compared to parallel imaging by itself. However, such temporal acceleration strategies prove difficult to combine with retrospectively gated cine imaging. The only currently published method to feature such combination, by Hansen et al. [Magn Reson Med 55 (2006) 85-91] tends to be associated with prohibitively long reconstruction times. The goal of the present work was to develop a retrospectively gated cardiac cine method that features both parallel imaging and temporal acceleration, capable of achieving significant acceleration factors on commonly available hardware and associated with reconstruction times short enough for practical use in a clinical context. Seven cardiac patients and a healthy volunteer were recruited and imaged, with acceleration factors of 3.5 or 4.5, using an eight-channel product cardiac array on a 1.5-T system. The prescribed FOV value proved slightly too small in three patients, and one of the patients had a bigemini condition. Despite these additional challenges, good-quality results were obtained for all slices and all patients, with a reconstruction time of 0.98±0.07 s per frame, or about 20 s for a 20-frame slice, using a single processor on a single PC. As compared to using parallel imaging by itself, the addition of a temporal acceleration strategy provided much resistance to artifacts.

[Perforation risk and patient age. Risk analysis in acute sigmoid diverticulitis]. / Perforationsrisiko und Patientenalter. Eine Risikoanalyse bei der akuten Sigmadivertikulitis.

INTRODUCTION: It is often postulated that younger patients with acute sigmoid diverticulitis (SD) have an increased risk of perforation which constitutes an indication for early surgery. The aim of this study was to correlate the severity of sigmoid diverticulitis with patient age in order to check the surgical indication in younger patients. PATIENTS AND METHODS: Patients with acute SD from January 1998 to June 2009 were included. Two age groups were distinguished: group I (GI) ≤40 years in age and group II (GII) >40 years. The perforation risk associated with first episode SD was determined by multivariate analysis. SD was classified according to Hansen and Stock (H/S). RESULTS: In the total cohort of 959 patients, including 86 in GI (8.9%) and 873 in GII (91.1%) 468 had a first episode, with 64 in GI (13.7%) and 404 in GII (86.3%). The proportion of first episodes was 74.4% in GI and 46.3% in GII (p<0.001). The perforation risk did not differ (H/S IIb: 29.7% in GI vs. 29.2% in GII, p=0.938; H/S IIc: 25% in GI vs. 25% in GII, p=1). Treatment regimes were (GI vs. GII) emergency operations 25% vs. 25% (p=1), elective operations 17.2% vs. 10% (p=0.096) and conservative treatment 57.8% vs. 64.9% (p=0.276). CONCLUSION: First episodes of SD were more frequent in younger patients (≤40) and did not involve a higher risk of perforation. The indication for treatment of acute SD should not be based on age but on the severity of inflammation and the individual situation of patients.

Functional connectivity metrics during stroke recovery.

We explore functional connectivity in nine subjects measured with 1.5T fMRI-BOLD in a longitudinal study of recovery from unilateral stroke affecting the motor area (Small et al., 2002). We found that several measures of complexity of covariance matrices show strong correlations with behavioral measures of recovery. In Schmah et al. (2010), we applied Linear and Quadratic Discriminants (LD and QD) computed on a principal components (PC) subspace to classify the fMRI volumes into "early" and "late" sessions. We demonstrated excellent classification accuracy with QD but not LD, indicating that potentially important differences in functional connectivity exist between the early and late sessions. Motivated by Mclntosh et al. (2008), who showed that EEG brain-signal variability and behavioral performance both increased with age during development, we investigated complexity of the covariance matrix for this longitudinal stroke recovery data set. We used three complexity measures: the sphericity index described by Abdi (2010); "unsupervised dimensionality", which is the number of PCs that minimizes unsupervised generalization error of a covariance matrix (Hansen et al., 1999); and "QD dimensionality", which is the number of PCs that minimizes the classification accuracy of QD. Although these approaches measure different kinds of complexity, all showed strong correlations with one or more behavioral tests: nine-hole peg test, hand grip test and pinch test. We could not demonstrate that either sphericity or unsupervised dimensionality were significantly different for the "early" and "late" sessions using a paired Wilcoxon test. However, the amount of relative behavioral improvement was correlated with sphericity of the overall covariance matrix (pooled across all sessions), as well as with the divergence of the eigenspectra between the "early" and "late" covariance matrices. Complexity measures that use the number of PCs (which optimize QD classification or unsupervised generalization) were correlated with the behavioral performance of the final session, but not with the relative improvement. These are suggestive, but limited, results given the sample size, restricted behavioral measurements and older 1.5T BOLD data sets. Nevertheless, they indicate one potentially fruitful direction for future data-driven fMRI studies of stroke recovery in larger, better-characterized longitudinal stroke data sets recorded at higher field strength. Finally, we produced sensitivity maps (Kjems et al., 2002) corresponding to both linear and quadratic discriminants for the "early" vs. "late" classification. These maps measure the influence of each voxel on the class assignments for a given classifier. Differences between the scaled sensitivity maps for the linear and quadratic discriminants indicate brain regions involved in changes in functional connectivity. These regions are highly variable across subjects, but include the cerebellum and the motor area contralateral to the lesion.

Weakened feedback abolishes neural oblique effect evoked by pseudo-natural visual stimuli in area 17 of the cat.

The psychological oblique effect, a well-known phenomenon that humans and some mammals are more visually sensitive to cardinal (vertical and horizontal) contours than to oblique ones, has commonly been associated with the overrepresentation of cardinal orientations in the visual cortex. In contrast to the oblique effect, however, Essock et al. [E.A. Essock, J.K. DeFord, B.C. Hansen, M.J. Sinai, Oblique stimuli are seen best (not worst!) broad-band stimuli: a horizontal effect, Vision Res. 43 (2003) 1329-1335] reported a psychological 'horizontal effect', in which visual stimuli dominated by oblique orientations were best perceived by human subjects when tested with unique natural broad-band stimuli. In this study, using optical imaging and the similar visual stimuli, we found an overrepresentation of cardinal orientations, i.e. the neural oblique effect, but not 'horizontal effect', in area 17 of the cat. In addition, the oblique effect was abolished by GABA administration in area 21a due to the preferred orientation shifting (6.0%) and decrease of orientation selectivity strength of neurons (26.9%) in area 17. These results indicate a neuronal basis of the oblique effect when animals watch a more natural scene, whereas no evidence was found for the 'horizontal effect'.

The impact of temporal regularization on estimates of the BOLD hemodynamic response function: a comparative analysis.

In fMRI data analysis it has been shown that for a wide range of situations the hemodynamic response function (HRF) can be reasonably characterized as the impulse response function of a linear and time invariant system. An accurate and robust extraction of the HRF is essential to infer quantitative information about the relative timing of the neuronal events in different brain regions. When no assumptions are made about the HRF shape, it is most commonly estimated using time windowed averaging or a least squares estimated general linear model based on either Fourier or delta basis functions. Recently, regularization methods have been employed to increase the estimation efficiency of the HRF; typically these methods produce more accurate HRF estimates than the least squares approach [Goutte, C., Nielsen, F.A., Hansen, L.K., 2000. Modeling the Haemodynamic Response in fMRI Using Smooth FIR Filters. IEEE Trans. Med. Imag. 19(12), 1188-1201.]. Here, we use simulations to clarify the relative merit of temporal regularization based methods compared to the least squares methods with respect to the accuracy of estimating certain characteristics of the HRF such as time to peak (TTP), height (HR) and width (W) of the response. We implemented a Bayesian approach proposed by Marrelec et al. [Marrelec, G., Benali, H., Ciuciu, P., Pelegrini-Issac, M., Poline, J.-B., 2003. Robust Estimation of the Hemodynamic Response Function in Event-Related BOLD fMRI Using Basic Physiological Information. Hum. Brain Mapp. 19, 1-17., Marrelec, G., Benali, H., Ciuciu, P., Poline, J.B. Bayesian estimation of the hemodynamic of the hemodynamic response function in functional MRI. In: R. F, editor; 2001; Melville. p 229-247.] and its deterministic counterpart based on a combination of Tikhonov regularization [Tikhonov, A.N., Arsenin, V.Y., 1977. Solution of ill-posed problems. Washington DC: W.H. Winston.] and generalized cross-validation (GCV) [Wahba, G., 1990. Spline Models for Observational Data. Philadelphia: SIAM.] for selecting the regularization parameter. The performance of both methods is compared with least square estimates as a function of temporal resolution, color and strength of the noise, and the type of stimulus sequences used. In almost all situations, under the considered assumptions (e.g. linearity, time invariance and smooth HRF), the regularization-based techniques more accurately characterize the HRF compared to the least-squares method. Our results clarify the effects of temporal resolution, noise color, and experimental design on the accuracy of HRF estimation.

Interactive optical trapping shows that confinement is a determinant of growth in a mixed yeast culture.

Applying a newly developed user-interactive optical trapping system, we controllably surrounded individual cells of one yeast species, Hanseniaspora uvarum, with viable cells of another yeast species, Saccharomyces cerevisiae, thus creating a confinement of the former. Growth of surrounded and non-surrounded H. uvarum cells was followed under a microscope by determining their generation time. The average generation time of surrounded H. uvarum cells was 15% higher than that of non-surrounded cells, thereby showing that the confinement imposed by viable S. cerevisiae cells on H. uvarum inhibits growth of the latter. This study is the first to demonstrate that confinement is a determinant of growth in a microbial ecosystem.

[Image analysis to quantify S100-positive dendritic cells in leprosy-affected skin]. / Utilización de análisis de imágenes para cuantificar células dendríticas S100 positivas en piel con lepra.

A morphometric analysis of skin dendritic cells was done on biopsies of patients with different forms of leprosy. An anti S100 antibody was used to determine dendritic cell quantity and extension. Patients with a better immune response to the bacillus showed a greater number of dendritic cells in the cases of dimorphic tuberculoid leprosy and tuberculoid leprosy. This result contrasted with that from patients with dimorphic lepromatous leprosy and lepromatous leprosy.

Atomic force microscopy as a tool for biomedical and biotechnological studies.

This work presents different applications in progress with the aid of the atomic force microscopy (AFM) technique for biomedical and biotechnological applications, comprising both the acquisition of three-dimensional images and spectroscopic force measurements, in the following systems: first, low-density lipoprotein (LDL)-glycosaminoglycans; second, lectins-polysaccharides; third, mycobacterium leprae cellular wall and Vesicular Stomatites Virus (VSV) with fibronectin laminin, and lipidic membranes; fourth, DNA-complex; and fifth, actin, as well as the development of surface functionalizing protocols and image restoration by means of mathematical techniques.

Cryo-electron microscopic localization of protein L7/L12 within the Escherichia coli 70 S ribosome by difference mapping and Nanogold labeling.

The Escherichia coli ribosomal protein L7/L12 is central to the translocation step of translation, and it is known to be flexible under some conditions. The assignment of electron density to L7/L12 was not possible in the recent 2.4 A resolution x-ray crystallographic structure (Ban, N., Nissen, P., Hansen, J., Moore, P. B., and Steitz, T. A. (2000) Science 289, 905-920). We have localized the two dimers of L7/L12 within the structure of the 70 S ribosome using two reconstitution approaches together with cryo-electron microscopy and single particle reconstruction. First, the structures were determined for ribosomal cores from which protein L7/L12 had been removed by treatment with NH(4)Cl and ethanol and for reconstituted ribosomes in which purified L7/L12 had been restored to core particles. Difference mapping revealed that the reconstituted ribosomes had additional density within the L7/L12 shoulder next to protein L11. Second, ribosomes were reconstituted using an L7/L12 variant in which a single cysteine at position 89 in the C-terminal domain was modified with Nanogold (Nanoprobes, Inc.), a 14 A gold derivative. The reconstruction from cryo-electron microscopy images and difference mapping placed the gold at four interfacial positions. The finding of multiple sites for the C-terminal domain of L7/L12 suggests that the conformation of this protein may change during the steps of elongation and translocation.

Leydig cell hyperplasia and the maintenance of bone volume: bone histomorphometry and testicular histopathology in 29 male leprosy autopsy cases.

This study was conducted to determine if osteoporosis in male leprosy patients is caused by testicular atrophy. Bone volume (BV/TV), trabecular number (TbN), trabecular thickness (TbTh), and trabecular separation (TbSp) were measured in two areas in decalcified paraffin sections of lumbar bones from 29 male leprosy and 6 male nonleprosy autopsy cases. We found significant differences in the average BV/TV measurements among the 7 patients with nodular Leydig cell hyperplasia (BV/TV 12.24%) and the 22 patients without hyperplasia (BV/TV 7.35%) and 6 patients without leprosy (BV/TV 12.98%). Bone volume was maintained in patients with nodular Leydig cell hyperplasia, and we determined no clinical factor other than the Leydig cell hyperplasia that reflected the bone volume. The osteoporosis of male leprosy patients was attributed to secondary gonadal dysfunction due to testicular atrophy, and Leydig cell hyperplasia appears to preserve bone volume.