Pronounced Atrophy Research Articles

Increased blood oxidative stress in experimental menopause rat model: the effects of vitamin A low‐dose supplementation upon antioxidant status in bilateral ovariectomized rats

Menopause has been reported to be associated with increased oxidative stress and metabolic disorders among women worldwide. Disarrangements in the redox state similar to those observed in women during the decline of ovarian hormonal activity can be obtained experimentally through rat bilateral ovariectomy. The search for alternative treatments to improve life quality in postmenopausal woman is really important. The aim of this study was to evaluate biochemical and oxidative stress parameters that distinguish sham-operated female rats from Wistar rats bilaterally ovariectomized (OVX). Additionally, we have also investigated the effects of retinol palmitate (a vitamin A supplement) low-dose supplementation (500 or 1500 IU/kg/day, during 30 days) upon blood and plasma antioxidant status in OVX rats. Ovariectomy caused an increase in body weight gain, pronounced uterine atrophy, decreased plasma triglycerides and increased total cholesterol levels, and reduced acid uric content. Moreover, we found increased blood peroxidase activities (catalase and glutathione peroxidase), decreased plasma non-enzymatic antioxidant defenses total reactive antioxidant potential and total antioxidant reactivity, decreased protein and non-protein SH levels, accompanied by increased protein oxidative damage (carbonyl). In addition, vitamin A low-dose supplementation was capable to ameliorate antioxidant status in OVX rats, restoring both enzymatic and non-enzymatic defenses, promoting reduction in plasma SH content, and decreasing protein oxidative damage levels. This is the first work in the literature showing that vitamin A at low dose may be beneficial in the treatment of menopause symptoms. Further studies will be made to better understand the effects of vitamin A supplementation in menopause rat model.

Effect of branched-chain amino acid supplementation during unloading on regulatory components of protein synthesis in atrophied soleus muscles

Maintenance of skeletal muscle mass depends on the equilibrium between protein synthesis and protein breakdown; diminished functional demand during unloading breaks this balance and leads to muscle atrophy. The current study analyzed time-course alterations in regulatory genes and proteins in the unloaded soleus muscle and the effects of branched-chain amino acid (BCAA) supplementation on muscle atrophy and abundance of molecules that regulate protein turnover. Short-term (6days) hindlimb suspension of rats resulted in significant losses of myofibrillar proteins, total RNA, and rRNAs and pronounced atrophy of the soleus muscle. Muscle disuse induced upregulation and increases in the abundance of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), increases in gene and protein amounts of two ubiquitin ligases (muscle RING-finger protein 1 and muscle atrophy F-box protein), and decreases in the expression of cyclin D1, the ribosomal protein S6 kinase 1, the mammalian target of rapamycin (mTOR), and ERK1/2. BCAA addition to the diet did not prevent muscle atrophy and had no apparent effect on regulators of proteasomal protein degradation. However, BCAA supplementation reduced the loss of myofibrillar proteins and RNA, attenuated the increases in 4E-BP1, and partially preserved cyclin D1, mTOR and ERK1 proteins. These results indicate that BCAA supplementation alone does not oppose protein degradation but partly preserves specific signal transduction proteins that act as regulators of protein synthesis and cell growth in the non-weight-bearing soleus muscle.

REHABILITATION OF SEVERELY ATROPHIED UPPER JAW WITH INTRAOSSAL DENTAL IMPLANTS - clinical case

Objective: The purpose of this presentation is to show the difficulty in prosthetization of a clinical case with a pronounced atrophy of the upper jaw and the various types and nature of restrictions imposed by the requirements of the patient. Methods: The clinical analysis, surgical protocol and prosthetic solution are presented in the treatment of 72 yearold woman with a pronounced atrophy of the upper jaw. OPG, standard CT of the upper jaw was used in the planning and a special surgical template was fabricated, helping us to find intraoperatively the exact locations of implants. The preliminary analysis of the number, height and diameter of intraossal implants helped us to find the exact prosthetic solution in this clinical case. The preparation of the implant bed was done by conical osteotomy in order to expand and condense the existing bone, which allowed us to use endoossal implants with a possible maximum size in a very limited maxillary volume and the reluctance of the patient to use other methods and surgical techniques. Conical threaded and self-tapping intraossal implants were used, placed according to a classic two-stage methodology with a flap and a long-term functional loading after a period of four months. Results and Conclusion: The applied surgical and prosthetic solution allowed us to achieve a good functional and aesthetic rehabilitation in this case of severe atrophy of the upper jaw, following a number of restrictions imposed on us by the reluctance of the patient to use other surgical solutions. This shows that in the case of severe atrophy of the upper jaw, a good clinical result can be achieved. For this reason, the use of CT, a well-planned surgical template, sufficient preparation, the maximum use of available bone volume and the choice of a good prosthetic solution is very important.

The human G93A-SOD1 mutation in a pre-symptomatic rat model of amyotrophic lateral sclerosis increases the vulnerability to a mild spinal cord compression

BackgroundTraumatic injuries can undermine neurological functions and act as risk factors for the development of irreversible and fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). In this study, we have investigated how a mutation of the superoxide dismutase 1 (SOD1) gene, linked to the development of ALS, modifies the acute response to a gentle mechanical compression of the spinal cord. In a 7-day post-injury time period, we have performed a comparative ontological analysis of the gene expression profiles of injured spinal cords obtained from pre-symptomatic rats over-expressing the G93A-SOD1 gene mutation and from wild type (WT) littermates.ResultsThe steady post-injury functional recovery observed in WT rats was accompanied by the early activation at the epicenter of injury of several growth-promoting signals and by the down-regulation of intermediate neurofilaments and of genes involved in the regulation of ion currents at the 7 day post-injury time point. The poor functional recovery observed in G93A-SOD1 transgenic animals was accompanied by the induction of fewer pro-survival signals, by an early activation of inflammatory markers, of several pro-apoptotic genes involved in cytochrome-C release and by the persistent up-regulation of the heavy neurofilament subunits and of genes involved in membrane excitability. These molecular changes occurred along with a pronounced atrophy of spinal cord motor neurones in the G93A-SOD1 rats compared to WT littermates after compression injury.ConclusionsIn an experimental paradigm of mild mechanical trauma which causes no major tissue damage, the G93A-SOD1 gene mutation alters the balance between pro-apoptotic and pro-survival molecular signals in the spinal cord tissue from the pre-symptomatic rat, leading to a premature activation of molecular pathways implicated in the natural development of ALS.

Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume?

Normal aging is accompanied by global as well as regional structural changes. While these age-related changes in gray matter volume have been extensively studied, less has been done using newer morphological indexes, such as cortical thickness and surface area. To this end, we analyzed structural images of 216 healthy volunteers, ranging from 18 to 87 years of age, using a surface-based automated parcellation approach. Linear regressions of age revealed a concomitant global age-related reduction in cortical thickness, surface area and volume. Cortical thickness and volume collectively confirmed the vulnerability of the prefrontal cortex, whereas in other cortical regions, such as in the parietal cortex, thickness was the only measure sensitive to the pronounced age-related atrophy. No cortical regions showed more surface area reduction than the global average. The distinction between these morphological measures may provide valuable information to dissect age-related structural changes of the brain, with each of these indexes probably reflecting specific histological changes occurring during aging.

Equine protozoal myeloencephalitis due to Neospora hughesi and equine motor neuron disease in a mule

A 23-year-old female mule was presented for bilateral ocular abnormalities and an abnormal pelvic limb gait. Anisocoria, unilateral enophthalmos, medial strabismus, ptosis, pupillary light reflex deficits, and bilateral reticulated pigmentary retinopathy were observed on ophthalmic examination. Neurologic abnormalities included right-sided facial nerve paralysis, extensive symmetric muscle atrophy, and asymmetric pelvic limb ataxia with an abnormal pelvic limb gait. A positive titer (1:40) for equine protozoal myeloencephalitis (EPM) associated with Neospora hughesi was obtained from cerebrospinal fluid with minimal (<1 red blood cell/microL) blood contamination. Muscle biopsies of the sacrocaudalis dorsalis medialis muscle revealed predominantly type I neurogenic muscle atrophy, consistent with a diagnosis of equine motor neuron disease (EMND). Treatment included a 2-month course of ponazuril (5 mg/kg PO q24 h), vitamin E (8000 IU PO q24 h), and selenium (2 mg PO q24 h). Clinical improvement was not observed after 2 months although the mule remained stable. Clinical deterioration was reported upon discontinuation of the ponazuril after a 2-month course. Concurrent disease with EPM associated with N. hughesi and EMND should be considered in cases demonstrating cranial nerve abnormalities, pronounced symmetric muscle atrophy, unusual asymmetric gait abnormalities, and reticulated pigmentary retinopathy.

A New Semi-quantitative Approach for Analysing 3T Diffusion Tensor Imaging of Optic Fibres and Its Clinical Evaluation in Glaucoma

Diffusion tensor imaging can depict rarefaction of the optical fibers. Manual segmentation is time consuming. The purposes of the study were (1) to present a new semiquantitative segmentation approach for analyzing 3-T diffusion tensor imaging of optical fibers and (2) to clinically test the new approach by comparing optic fiber rarefaction in patients with glaucoma to that in age-matched, healthy controls. To perform semiautomated and quantitative segmentation of the optical radiation, a Mathcad-based software program was developed. The results were compared to the manual evaluation of the images performed by two experienced neuroradiologists. The eyes of 42 subjects (22 patients with glaucoma and 20 controls) aged 37 to 86 years were assessed in full ophthalmologic examinations. Magnetic resonance imaging was performed using a 3-T high-field scanner. The evaluation using the new approach matched 94% with manually acquired rarefaction of the optical radiation; Cronbach's α was >0.81 for calculation of the manually and semiautomatically derived volumes. The new approach seems to be robust and is clearly faster compared to the more tedious manual segmentation. Using diffusion tensor imaging at 3 T, it could be shown that there was increasing atrophy of the optical radiation (fourth neuron) with increasing age in patients with glaucoma. Compared to age-matched, healthy patients, more pronounced atrophy of the fourth neuron was found in patients with glaucoma.

Inhibitory effects of Japanese apricot (Prunus mume Siebold et Zucc.; Ume) on Helicobacter pylori-related chronic gastritis

We investigated the correlation between Japanese apricot (JA) intake and Helicobacter pylori-related chronic atrophic gastritis (CAG). A questionnaire was administered and serum anti-H. pylori IgG antibodies measured in 1358 asymptomatic adults. The subjects were divided into high-intake and low-intake groups. Histological and serological evaluation of H. pylori-related CAG was performed in 68 non-elderly volunteers. The H. pylori-negative rate did not differ significantly between the high-intake and low-intake groups. Mean antibody titers were lower in the high-intake group, but the difference was not significant. There was no significant difference in the rate of H. pylori infection on the basis of JA intake when subjects were stratified by age. Among H. pylori-positive non-elderly subjects, antibody titers were significantly lower in the high-intake group (P=0.041). Endoscopic tissue biopsy from the 68 volunteers showed less H. pylori bacterial load and mononuclear infiltration irrespective of gastric site in the high-intake group. In the high-intake group, antral neutrophil infiltration was significantly less pronounced and corporal atrophy was less extensive. Serological evaluation using serum PG levels also confirmed these histopathological data. Our findings strongly indicate a preventive effect of JA intake on CAG by inhibiting H. pylori infection and reducing active mucosal inflammation.

Factors associated with voice therapy outcomes in the treatment of presbyphonia

Age, vocal fold atrophy, glottic closure pattern, and the burden of medical problems are associated with voice therapy outcomes for presbyphonia. Retrospective. Records of patients seen over a 3-year period at a voice center were screened. Inclusion criteria consisted of age over 55 years, primary complaint of hoarseness, presence of vocal fold atrophy on examination, and absence of laryngeal or neurological pathology. Videostroboscopic examinations on initial presentation were reviewed. Voice therapy outcomes were assessed with the American Speech-Language-Hearing Association National Outcomes Measurement System scale. Statistical analysis was performed with Spearman rank correlation and chi(2) tests. Sixty-seven patients were included in the study. Of the patients, 85% demonstrated improvement with voice therapy. The most common type of glottic closure consisted of a slit gap. Gender or age had no effect on voice therapy outcomes. Larger glottic gaps on initial stroboscopy examination and more pronounced vocal fold atrophy were weakly correlated with less improvement from voice therapy. A weak correlation was also found between the number of chronic medical conditions and poorer outcomes from voice therapy. The degree of clinician-determined improvement in vocal function from voice therapy is independent of patient age but is influenced by the degree of vocal fold atrophy, glottic closure pattern, and the patient's burden of medical problems.

Structural and Functional Hippocampal Changes in Multiple Sclerosis Patients with Intact Memory Function

To investigate changes in hippocampal functional connectivity and structural measures of hippocampal damage in multiple sclerosis (MS) patients with intact spatial memory, a cognitive domain frequently affected in progressive MS. The study protocol was approved by the institutional ethics review board; all subjects gave written informed consent prior to participation. Twenty-five MS patients with intact spatial memory function were compared with 30 age- and sex-matched controls. Hippocampal volume differences, based on manually drawn masks, were evaluated by using the Student t test. Additionally, focal hippocampal lesions and mean diffusivity were obtained as descriptive measures of structural hippocampal damage. Multiple regression analyses of the resting-state functional magnetic resonance (MR) imaging data were performed for each subject by using hippocampal time series. Between-group analyses were conducted with a mixed-effects model, corrected for multiple comparisons by a cluster defining threshold level of z = 2 and a corrected cluster size significance level of P < .05. Right hippocampal volume was significantly lower in MS patients as compared with controls (P < .01). Left hippocampal volume was also lower in MS patients compared with controls, but not significantly so (P = .09). Resting-state functional connectivity between the hippocampus and its anatomic input or target areas, including the anterior cingulate gyrus, thalamus, and prefrontal cortex, were significantly decreased in MS patients. Decreased hippocampal functional connectivity was more pronounced in a subgroup of MS patients with hippocampal atrophy, although subtle decreases of functional connectivity were also found in patients with normal hippocampal volume. In MS patients, substantial abnormalities of hippocampal functional connectivity are already present before spatial memory function is impaired, especially in those patients with more pronounced hippocampal atrophy. Longitudinal studies should now assess whether these functional connectivity and structural changes may precede memory impairment in MS.

Prevention of muscle fibers atrophy during gravitational unloading: The effect of l-arginine administration

Gravitational unloading results in pronounced atrophy of m.soleus. Probably, the output of NO is controlled by the muscle activity. We hypothesized that NO may be involved in the protein metabolism and increase of its concentration in muscle can prevent atrophic changes induced by gravitational unloading. In order to test the hypothesis we applied NO donor l-arginine during gravitational unloading. 2.5-month-old male Wistar rats weighing 220–230g were divided into sedentary control group (CTR, n=7), 14-day hindlimb suspension (HS, n=7), 14 days of hindlimb suspension+ l-arginine (HSL, n=7) (with a daily supplementation of 500 mg/kg wt l-arginine) and 14 days of hindlimb suspension+ l-NAME (HSN, n=7) (90 mg/kg wt during 14 days). Cross sectional area (CSA) of slow twitch (ST) and fast twitch (FT) soleus muscle fibers decreased by 45% and 28% in the HS group ( p<0.05) and 40% and 25% in the HSN group, as compared to the CTR group ( p<0.05), respectively. CSA of ST and FT muscle fibers were 25% and 16% larger in the HSL group in comparison with the HS group ( p<0.05), respectively. The atrophy of FT muscle fibers in the HSL group was completely prevented since FT fiber CSA had no significant differences from the CTR group. In HS group, the percentage of fibers revealing either gaps/disruption of the dystrophin layer of the myofiber surface membrane increased by 27% and 17%, respectively, as compared to the controls (CTR group, p<0.05). The destructions in dystrophin layer integrity and reductions of desmin content were significantly prevented in HSL group. NO concentration decreased by 60% in the HS group (as well as HSN group) and at the same time no changes were detectable in the HSL group. This fact indicates the compensation of NO content in the unloaded muscle under l-arginine administration. The levels of atrogin-1 mRNA were considerably altered in suspended animals (HS group: plus 27%, HSL group: minus 13%) as compared to the control level. Conclusion: l-arginine administration allows maintaining NO concentration in m.soleus at the level of cage control group, prevents from dystrophin layer destruction, decreases the atrogin mRNA concentration in the muscle and atrophy level under gravitational unloading.

Loss of word-meaning with spared object semantics in a case of mixed primary progressive aphasia

This article provides a detailed assessment of patient HT with a history of progressive language deterioration of approximately 6years presenting now as a fluent jargon aphasic with severe impairment of both speech production and comprehension. Neuropsychological testing of non-verbal cognitive functions showed no impairment, leading to the assumption of primary progressive aphasia (PPA). Contrary to the clinical criteria of the known PPA-subtypes there was nearly parallel decline of word comprehension and motor speech. HT also showed a significant dissociation between verbal and non-verbal semantic abilities resulting in severely impaired word comprehension with object semantics relatively spared. MRI scanning revealed pronounced focal atrophy of the left anterior temporal lobe and the left perisylvian region with relatively spared right temporal involvement. The clinical diagnostic criteria for PPA-subtypes do not seem to apply to the language features shown by our patient. The similarities and distinctions to semantic dementia and progressive non-fluent aphasia (PNFA) as subtypes of PPA will be discussed. The distinction between PNFA and SD may represent an oversimplification of the clinical presentations of PPA. It is also suggested that a mixed version of primary progressive aphasia should be taken into consideration as accepted clinical subtype.

Association of CSF total tau and phospho-tau (181) with cerebral atrophy in mild cognitive impairment and Alzheimer's disease

Objective: To examine the association of levels of total tau (t-tau) and phospho-tau (p-tau) 181 with brain morphology in mild cognitive impairment as defined by the concept of aging-associated cognitive decline (AACD) and Alzheimer's disease (AD). Method: Twenty-three subjects with AACD, 16 with AD and 15 healthy controls underwent magnetic resonance imaging and lumbar puncture. Voxel-based morphometry (VBM) was performed to investigate the association between CSF tau levels and cerebral gray matter density throughout the entire brain. Results: VBM revealed both, elevated t-tau and p-tau181 concentrations to be associated with reduced gray matter density in temporal, parietal and frontal regions. Within the AACD group, elevated CSF levels of p-tau181 (but not t-tau) were correlated with a pronounced atrophy in the right hippocampus. Conclusion: Elevated CSF levels of t-tau and p-tau181 reflect degenerative processes in AD typical cortical regions. Our findings in AACD subjects support the hypothesis that p-tau181 might be more specifically related to neurodegenerative changes in early AD.

Glycemic status and brain injury in older individuals: the age gene/environment susceptibility-Reykjavik study.

OBJECTIVETo examine the association of glycemic status to magnetic resonance imaging indicators of brain pathological changes.RESEARCH DESIGN AND METHODSThis was a cross-sectional, population-based study of 4,415 men and women without dementia (mean age 76 years) participating in the Age Gene/Environment Susceptibility–Reykjavik Study. Glycemic status groups included the following: type 2 diabetes (self-report of diabetes, use of diabetes medications, or fasting blood glucose ≥7.0 mmol/l [11.1%]); impaired fasting glucose (IFG) (fasting blood glucose 5.6–6.9 mmol/l [36.2%]); and normoglycemic (52.7%). Outcomes were total brain volume, white and gray matter volume, white matter lesion (WML) volume, and presence of cerebral infarcts.RESULTSAfter adjustment for demographic and cardiovascular risk factors, participants with type 2 diabetes had significantly lower total brain volume (72.2 vs. 71.5%; P < 0.001) and lower gray and white matter volumes (45.1 vs. 44.9%, P < 0.01 and 25.7 vs. 25.3%, P < 0.001, respectively) and were more likely to have single (odds ratio 1.45 [95% CI 1.14–1.85]) or multiple (2.27 [1.60–3.23]) cerebral infarcts compared with normoglycemic participants. Longer duration of type 2 diabetes was associated with lower total brain volume and gray and white matter volume, higher WML volume (all Ptrend < 0.05), and a greater likelihood of single and multiple cerebral infarcts (all Ptrend < 0.01).CONCLUSIONSType 2 diabetic participants have more pronounced brain atrophy and are more likely to have cerebral infarcts. Duration of type 2 diabetes is associated with brain changes, suggesting that type 2 diabetes has a cumulative effect on the brain.

Effects of demographic factors on cortical thickness in Alzheimer's disease

The aim of this study was to investigate the effect of demographic factors (age of onset, sex and years of education) on the distribution of cortical thickness in a large sample of patients with Alzheimer's disease (AD). The study participants consisted of 193 AD patients and 142 controls with no cognitive impairment (NCI) that were measured with cortical thickness across the entire brain. The effects of demographic factors on cortical thickness were analyzed by applying linear regression after controlling confounding factors. Older individuals in NCI group showed more cortical thinning in frontal, temporal association cortices and insula than younger participants. Early onset AD was associated with cortical thinning in the parietal lobe, whereas late onset AD was associated with cortical thinning in the medial temporal region. The NCI group demonstrated sex-related differences in cortical thickness, although those differences were not present in the AD group. While the education effect was absent in NCI individuals, high levels of education in the AD group correlated with cortical thinning in the frontal and temporoparietal association cortices. Our results show that AD with earlier onset and higher education had suffered more pronounced cortical atrophy in specific parts of the brain than their counterparts, which may be related to cognitive reserve theory.

Clinical Relevance of Neuromuscular Findings and Abnormal Movement Patterns: A Comparison between Focal Hand Dystonia and Upper Extremity Entrapment Neuropathies

Narrative Review Patients with focal hand dystonia and upper extremity entrapment neuropathies may present with similar symptoms and risk factors making it difficult to distinguish between the two diagnoses. Evaluating for the presence of neuromuscular findings and abnormal movement patterns can help assist the hand therapist in identifying the presence of focal hand dystonia or peripheral motor axon involvement in the absence of pronounced muscle atrophy. The purposes of this review article are twofold. First, to describe selected neuromuscular signs and symptoms characteristic of patients presenting with repetitive overuse syndromes of the upper limb leading to either a nerve entrapment syndrome or a focal hand dystonia. The selected topics will be limited to an overview of ectopic neuronal activity with an emphasis on fasciculations, muscle spasms/cramps, and sensation (including pain). Second, the article will conclude with a brief synopsis of focal hand dystonia and compression neuropathies, highlighting general assessment and treatment principles.

Brainstem atrophy on routine MR study in pallidopontonigral degeneration

Sirs, Pallidopontonigral degeneration (PPND) is an autosomal dominant inherited disorder which belongs to the spectrum of frontotemporal dementia linked to chromosome 17 (FTDP-17). It is caused by the N279K mutation in the gene encoding the microtubule-associated protein tau on chromosome 17 [3, 11]. Clinically, PPND is characterized by early and prominent parkinsonism with mild cognitive and behavioral changes, with some differences in clinical presentation between four branches of the PPND kindred [9, 11, 13]. Pathologically, PPND presents with neuronal loss and gliosis, most pronounced in the globus pallidus, pontine and mesencephalic tegmentum and substantia nigra [7, 13]. Immunohistochemistry reveals extensive neuronal and glial tau pathology [7, 8]. Routine magnetic resonance (MR) scanning performed in PPND patients reveals bilateral cortical atrophy, ventricular enlargement, narrowing of the substantia nigra pars compacta and atrophy of the pontine tegmentum [4]. Arvanitakis et al. [1] stressed prominent temporal atrophy in five affected PPND subjects; this was also seen in one asymptomatic N279K mutation carrier who converted to affected status 8 months after the MR study. In some FTDP-17 cases with the MAPT mutation, atrophy of the midbrain and pons was observed at autopsy [14]. Our previous pathological and MR studies confirmed profound brainstem atrophy in progressive supranuclear palsy (PSP) [10, 12]. Because PPND shares some clinical and pathological features with other atypical parkinsonian disorders [1, 8, 9], we decided to examine whether brainstem atrophy is also a feature of PPND and, if so, whether this feature may facilitate the differential diagnosis of PPND. We examined six pathologically confirmed PPND patients [three males, symptom duration 7 ± 3 years, age at death (AAD) 53 ± 5 years] and a historical series [10] of five pathologically confirmed PSP patients [three males, symptom duration 6 ± 2 years, AAD 77 ± 8 years]. The control group consisted of 25 healthy subjects, age and gender-matched to the PPND patients. The time interval between MR imaging and death was 50 ± 13 months in the PPND group and 45 ± 8 months in the PSP group. Six morphometric parameters of the midbrain (MB) and pons were measured on T1-weighted midsagittal and axial MR scans with Image Analyzer software. The technique of MR scanning and image analysis have been described in detail earlier [10]. The Mann–Whitney test was applied. A P value\0.05 was considered to be significant. Results of the study are summarized in Table 1. Midsagittal midbrain (MB) area and the MB area/pons area ratio were significantly smaller in PPND patients than in the controls (Fig. 1a, b), with the PSP cases showing even more pronounced midbrain atrophy. Other measurements did not differ between the PSP and PPND patients. Mean J. L. Slowinski K. J. Schweitzer A. Imamura R. J. Uitti A. J. Strongosky Z. K. Wszolek (&) Department of Neurology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224, USA e-mail: wszolek.zbigniew@mayo.edu

A Requirement for Cyclin-Dependent Kinase 6 in Thymocyte Development and Tumorigenesis

Cyclin-dependent kinase 6 (CDK6) promotes cell cycle progression and is overexpressed in human lymphoid malignancies. To determine the role of CDK6 in development and tumorigenesis, we generated and analyzed knockout mice. Cdk6-deficient mice show pronounced thymic atrophy due to reduced proliferative fractions and concomitant transitional blocks in the double-negative stages. Using the OP9-DL1 system to deliver temporally controlled Notch receptor-dependent signaling, we show that CDK6 is required for Notch-dependent survival, proliferation, and differentiation. Furthermore, CDK6-deficient mice were resistant to lymphomagenesis induced by active Akt, a downstream target of Notch signaling. These results show a critical requirement for CDK6 in Notch/Akt-dependent T-cell development and tumorigenesis and strongly support CDK6 as a specific therapeutic target in human lymphoid malignancies.

A Rotterdam controversy: the aetiology of the cryptorchid hypothalamo‐pituitary‐testicular axis

Dear Sir, In their contribution, Pierik et al. (2008) found in 43 cryptorchid infants studied, testosterone and free-androgens deficiency indicating a disturbance of testicular function that was already evident early after birth. Twenty years earlier one of the co-authors in this paper analysed 48 cryptorchid infants and came to different conclusion that “during the first year of life boys with cryptorchidism have no functional insufficiency of hypothalamus-pituitary-testis axis (HPG) or disorders in testosterone biosynthesis” (De Muinck Keizer-Schrama et al., 1988). Surprisingly, no annotation regarding this controversy was made in their paper. We would question what has changed in the past 20 years that led them to this observation of Leydig cell dysfunction. Is the ethnic heterogeneity of cryptorchid boys responsible for the observation of the hypothalamo-pituitary-testicular axis insufficiency found in Turkish population? Or, could severity or bilaterality of cryptorchidism, which was not known for the majority of cases studied, be an explanation for the lower LH and FSH levels? During last 35 years it has been histology that contributed most in helping us to understand the aetiology of cryptorchidism. In 1975 we described pronounced Leydig cell atrophy starting in early infancy as the evidence to support the endocrinopathy as an etiologic factor of cryptorchidism (Hadziselimovic et al., 1975). Development of Ad spermatogonia from gonocytes, which takes place during first months of life, has been shown to be testosterone dependent and is disturbed in the majority of cryptorchid boys (Hadziselimovic et al., 2005; Zivkovic et al., 2007). Analysis of the contralateral descended testis in unilateral cryptorchidism demonstrated that cryptorchidism is a bilateral disease (Hadziselimovic et al., 2005; Zivkovic et al., 2007; Huff et al., 2001). Therefore, an examination of histology at the time of orchidopexy could help authors to better understand hypogonadotropic hypogonadism and explain the different ethnical observations.

Optical coherence tomography in multiple sclerosis

Axonal distribution within the retinal nerve fiber layer (RNFL) measured by optical coherence tomography (OCT) correlates with axonal viability and integrity. To investigate correlations between RNFL and MRI measures of axonal loss in MS patients. Fifty one remitting-relapsing MS patients, 20 with a history of optic neuritis (MS-ON), 31 without optic neuritis (MS N-ON), and 12 healthy control subjects (HC) were included in the study. RNFL was measured by OCT and brain atrophy was assessed by MRI. The average RNFL in the affected eye (AE) in the MS-ON group was significantly lower than the RNFL in the MS N-ON (p = 0.01) and in HC (p = 0.01). The average RNFL in the unaffected eye (UE) and RNFL in MS N-ON were also lower than HC, but this value did not achieve significance. In MS N-ON a lower average RNFL was associated with an increased T1 lesion volume (p = 0.03) and T2-lesion volume (p = 0.001). The RNFL in MS N-ON was also associated with a reduction of BPF and %gm fraction (p = 0.01, p = 0.02 respectively). In MS-ON there was a much weaker, non-significant correlation between RNFL thickness and T1, T2 volume, BPF, %gm and %wm fractions that might have resulted from a pronounced post-inflammatory local optic nerve atrophy in AE. The RNFL measured by OCT may be useful as a surrogate marker for assessment of brain atrophy in MS.