Morphological Brain Changes after Climbing to Extreme Altitudes-A Prospective Cohort Study.

BACKGROUND Findings of cerebral cortical atrophy, white matter lesions and microhemorrhages have been reported in high-altitude climbers. The aim of this study was to evaluate structural cerebral changes in a large cohort of climbers after an ascent to extreme altitudes and to correlate these findings with the severity of hypoxia and neurological signs during the climb. METHODS Magnetic resonance imaging (MRI) studies were performed in 38 mountaineers before and after participating in a high altitude (7126m) climbing expedition. The imaging studies were assessed for occurrence of new WM hyperintensities and microhemorrhages. Changes of partial volume estimates of cerebrospinal fluid, grey matter, and white matter were evaluated by voxel-based morphometry. Arterial oxygen saturation and acute mountain sickness scores were recorded daily during the climb. RESULTS On post-expedition imaging no new white matter hyperintensities were observed. Compared to baseline testing, we observed a significant cerebrospinal fluid fraction increase (0.34% [95% CI 0.10-0.58], p = 0.006) and a white matter fraction reduction (-0.18% [95% CI -0.32--0.04], p = 0.012), whereas the grey matter fraction remained stable (0.16% [95% CI -0.46-0.13], p = 0.278). Post-expedition imaging revealed new microhemorrhages in 3 of 15 climbers reaching an altitude of over 7000m. Affected climbers had significantly lower oxygen saturation values but not higher acute mountain sickness scores than climbers without microhemorrhages. CONCLUSIONS A single sojourn to extreme altitudes is not associated with development of focal white matter hyperintensities and grey matter atrophy but leads to a decrease in brain white matter fraction. Microhemorrhages indicative of substantial blood-brain barrier disruption occur in a significant number of climbers attaining extreme altitudes.

Dermatomyositis in a family of Working Kelpies

Eight members of a family of Working Kelpies were presented with signs compatible with dermatomyositis. Alopecia, crusts, ulcerations of the skin, depigmentation of nasal planum and lips, onychodystrophy and atrophy of the masticatory muscles were present with varying degree. Histopathology of the skin, but not from muscles was performed in three dogs and confirmed the clinical diagnosis. Different immunomodulating drugs (steroids, cyclosporine, mycophenolate mofetil, pentoxifylline, doxycyline/niacinamid, omega-3 fatty acids and vitamin E) were used with variable success. Dermatomyositis is an immune-mediated disease and a genetic predisposition is known in humans and certain canine breeds, mainly Shetland Sheepdogs and Collies, but also for the Beauceron. The responsible genes have not been identified so far. It is assumed that the Working Kelpie derives from the Collie which could explain a hereditary predisposition in the Kelpie.

Postnatal persistent infection with classical Swine Fever virus and its immunological implications.

It is well established that trans-placental transmission of classical swine fever virus (CSFV) during mid-gestation can lead to persistently infected offspring. The aim of the present study was to evaluate the ability of CSFV to induce viral persistence upon early postnatal infection. Two litters of 10 piglets each were infected intranasally on the day of birth with low and moderate virulence CSFV isolates, respectively. During six weeks after postnatal infection, most of the piglets remained clinically healthy, despite persistent high virus titres in the serum. Importantly, these animals were unable to mount any detectable humoral and cellular immune response. At necropsy, the most prominent gross pathological lesion was a severe thymus atrophy. Four weeks after infection, PBMCs from the persistently infected seronegative piglets were unresponsive to both, specific CSFV and non-specific PHA stimulation in terms of IFN-γ-producing cells. These results suggested the development of a state of immunosuppression in these postnatally persistently infected pigs. However, IL-10 was undetectable in the sera of the persistently infected animals. Interestingly, CSFV-stimulated PBMCs from the persistently infected piglets produced IL-10. Nevertheless, despite the addition of the anti-IL-10 antibody in the PBMC culture from persistently infected piglets, the response of the IFN-γ producing cells was not restored. Therefore, other factors than IL-10 may be involved in the general suppression of the T-cell responses upon CSFV and mitogen activation. Interestingly, bone marrow immature granulocytes were increased and targeted by the virus in persistently infected piglets. Taken together, we provided the first data demonstrating the feasibility of CSFV in generating a postnatal persistent disease, which has not been shown for other members of the Pestivirus genus yet. Since serological methods are routinely used in CSFV surveillance, persistently infected pigs might go unnoticed. In addition to the epidemiological and economic significance of persistent CSFV infection, this model could be useful for understanding the mechanisms of viral persistence.

Efficacy and safety of non-hormonal remedies for vaginal dryness: open, prospective, randomized trial

OBJECTIVES To prove non-inferiority of the first non-hormonal vaginal cream in Germany, Vagisan(®) Moisturising Cream (CREAM), compared to a non-hormonal vaginal gel (GEL) for vulvovaginal atrophy (VVA) symptom relief. METHOD This was a 12-week multicenter, open-label, prospective, randomized, two-period, cross-over phase-III trial. The primary endpoint was the cumulative VVA subjective symptom score of the respective treatment period. Secondary endpoints were assessment of single VVA subjective and objective symptoms, VVA objective symptom score, vaginal pH, safety parameters, overall assessment of efficacy, tolerability and evaluation of product properties. In total, 117 women were randomly allocated to either one of the two treatments, each administered for 4 weeks; 92 women were included in the per-protocol analysis (primary analysis). The main outcome measure was cumulative VVA subjective symptom score. RESULTS Regarding VVA symptom relief, results confirmed non-inferiority of CREAM compared to GEL and even indicated superiority of CREAM. Frequency and intensity of subjective symptoms and objective findings were clearly reduced, with CREAM showing better results compared to GEL. Mean VVA objective symptom score significantly decreased; improvement was significantly greater with CREAM. Vaginal pH decreased only following CREAM treatment. Tolerability was superior for CREAM: burning and itching, mostly rated as mild, occurred markedly less often with CREAM than with GEL. Overall satisfaction with treatment efficacy, tolerability and most product properties were rated significantly superior for CREAM. CONCLUSIONS Subjective and objective VVA symptoms were reliably and safely reduced by both non-hormonal topical products. However, efficacy and tolerability of CREAM were shown to be superior to GEL.

New associations of classic acute macular neuroretinopathy

PURPOSE: To describe novel underlying associations of classic acute macular neuroretinopathy (AMN). METHODS: Multimodal imaging case series evaluating patients with classic AMN lesions and previously unreported underlying aetiologies. RESULTS: Six patients were included (five women, one man, mean age 30±7 years). Mean distance best corrected visual acuity at initial presentation was 0.21±0.3 logMAR (mean Snellen acuity: 20/30, range 20/15-20/100) and at last follow-up visit 0.09±0.17 logMAR (Snellen acuity: 20/20, range 20/15-20/60). All cases but one had bilateral lesions and showed typical parafoveal hyporeflective lesions on infrared imaging, which corresponded to the hyper-reflectivity in the Henle's layer with attenuation of the external limiting membrane, the ellipsoid zone and interdigitation zone. Underlying diseases included thrombocytopenia and anaemia associated with dengue fever, acute lymphoblastic leukaemia, chronic kidney disease and ulcerative colitis, while Valsalva-like manoeuvre was found to be a potential trigger. Other novel associations included the use of lisdexamphetamine. CONCLUSIONS: Classic AMN may be associated with leukaemia, dengue fever, ulcerative colitis and chronic kidney disease, probably as a result of chorioretinal hypoxia in the setting of thrombocytopenia and anaemia. Adrenergic agonists such as lisdexamphetamine may also contribute to the manifestation of AMN.

Ranibizumab for subfoveal choroidal neovascularisation associated with Stargardt disease.

INTRODUCTION: To describe the clinical outcomes of intravitreal ranibizumab treatment for subfoveal choroidal neovascularisation (CNV) associated with Stargardt disease. METHODS: Prospective, interventional, case series. All patients underwent intravitreal ranibizumab injections following a pro re nata regimen with monthly examination, over a 24-month follow-up. RESULTS: Three eyes were included in the study. Best corrected visual acuity changed from 0.47±0.06 (mean±SD) at baseline to 0.90±0.17 LogMAR at the end of the 24-month follow-up. Overall, a mean number of 11 ranibizumab injections were administered in 24 months. Significant atrophic growth was detected in all cases, with the mean atrophy area increasing from 2.34±2.60 mm(2) (mean±SD) at baseline to 4.23±3.31 mm(2) at the end of the follow-up. CONCLUSIONS: Ranibizumab treatment can stop the CNV progression, but cannot ensure a significant visual improvement. Macular atrophy tends to significantly enlarge under ranibizumab treatment over the follow-up. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Involvement of lipocalin 2 in leukemia and breast cancer

Human lipocalin 2 is described as the neutrophil gelatinase-associated lipocalin (NGAL). The lipocalin 2 gene encodes a small, secreted glycoprotein that possesses a variety of functions, of which the best characterized function is organic iron binding activity. Elevated NGAL expression has been observed in many human cancers including breast, colorectal, pancreatic and ovarian cancers. I focused on the characterization of NGAL function in chronic myelogenous leukemia (CML) and breast cancer. Using the leukemic xenograft mouse model, we demonstrated that over-expression of NGAL in K562 cells, a leukemic cell line, led to a higher apoptotic rate and an atrophy phenotype in the spleen of inoculated mice compared to K562 cells alone. These results indicate that NGAL plays a primary role in suppressing hematopoiesis by inducing apoptosis within normal hematopoietic cells. In the breast cancer project, we analyzed two microarray data sets of breast cancer cell lines ( n = 54) and primary breast cancer samples (n = 318), and demonstrated that high NGAL expression is significantly correlated with several tumor characteristics, including negative estrogen receptor (ER) status, positive HER2 status, high tumor grade, and lymph node metastasis. Ectopic NGAL expression in non-aggressive (ZR75.1 and MCF7) cells led to aggressive tumor phenotypes in vitro and in vivo. Conversely, knockdown of NGAL expression in various breast cancer cell lines by shRNA lentiviral infection significantly decreased migration, invasion, and metastasis activities of tumor cells both in vitro and in vivo . It has been previously reported that transgenic mice with a mutation in the region of trans-membrane domain (V664E) of HER2 develop mammary tumors that progress to lung metastasis. However, we observed that genetic deletion of the 24p3 gene, a mouse homolog of NGAL, in HER2 transgenic mice by breeding with 24p3-null mice resulted in a significant delay of mammary tumor formation and reduction of lung metastasis. Strikingly, we also found that treatment with affinity purified 24p3 antibodies in the 4T1 breast cancer mice strongly reduced lung metastasis. Our studies provide evidence that NGAL plays a critical role in breast cancer development and progression, and thus NGAL has potential as a new therapeutic target in breast cancer.^

William Osler: Original Papers 1881-1897

Part 1: 1881-1888 On Some Points in the Etiology and Pathology of Ulcerative Endocarditis, 1881 On Certain Parasites in the Blood of the Frog, 1883 The Third Corpuscle of the Blood, 1883 On the Use of Arsenic in Certain Forms of Anaemia, 1886 Antifebrin, 1887 Case of Arterio-Venous Aneurism of the Axillary Artery and Vein of Fourteen Year's Duration, 1887 Typhilitis and Appendicitis, 1888 Part 2: 1889-1892 Annual Address - License to Practice 1889 Case of Syphiloma of the Cord of the Cauda Equina-Death From Diffuse Central Myelitis, 1889 On a Case of Simple Idiopathic Muscular Atrophy, Involving the Face and the Scapulo-Humeral Muscles, 1889 Note on Intra-Thoracic Growths Developing from the Thyroid Gland, 1889 On the Value of Laveran's Organisms in the Diagnosis of Malaria, 1889 On the Form of Convulsive Tic Associated with Corprolalia, Etc., 1890 A Case of Sensory Aphasia Word-blindness with Hemianopsia, 1891 Rudolf Virchow: The Man and the Student, 1891 The Healing of Tuberculosis, 1892 The Cold-Bath Treatment of Typhoid Fever, 1892 Part 3: 1893 Remarks on the Varieties of Chronic Chorea, and a Report Upon Two Families of the Hereditary Form, With One Autopsy, 1893 Note on Arsenical Neuritis Following the use of Fowler's Solution, 1893 Note on a Remarkable House Epidemic of Typhoid Fever, 1893 Cases of Sub-Phrenic Abscess, 1893 On Sporadic Cretinism in America, 1893 Notes on Tuberculosis in Children, 1893 Part 4: 1849-1895 Parotitis in Pneumonia, Case of Pericarditis Treated by Incision and Drainage, 1894 The Army Surgeon, 1894 Introductory Remarks to Course of Clinical Demonstrations on Typhoid Fever, 1894 Cancer of the Stomach with Very Rapid Course, 1895 Case of Sporadic Cretinism (Infantile Myxcedema) Treated Successfully with Thyroid Extract, 1895 Visible Contractile Tumour of the Pylorus Following Ulcer of the Stomach, 1895 On the Association of Enormous Heart Hypertrophy, Chronic Proliferative Peritonitis, and Recurring Ascites, with Adherent Pericardium, 1895 Teaching and Thinking the Two Functions of a Medical School, 1895 The Practical Value of Laveran's Discoveries, 1895 Part 5 1896 Addison's Disease, 1896 On Six Cases of Addison's Disease, 1896 Hemiplegia in Typhoid Fever Thomas Dover (of Dover's Powder) Physician and Buccaneer, 1896 John Keats The Apothecary Poet, 1896 On The Classification of the Tics or Habit Movements, 1896 The Cerebral Complication of Raynaud's Disease, 1896 Part 6: 1897 On Certain Features in the Prognosis of Pneumonia, 1897 Clinical Lecture on Mitral Stenosis - Sudden Death - Ball Thrombus in the Left Auricle, 1897 The Diagnosis of Malarial Fever, 1897 The Functions of a State Faculty (President's Address), 1897 A Clinical Lecture on The Ball-Valve Gall-Stone in the Common Duct, 1897 Pneumonia (Review of Cases studied), 1897 Internal Medicine as a Vocation, 1897 Back Notes

Toxina botulínica para la secreción descontrolada de saliva : presentación de un caso

La neurotoxina botulínica es producida por la bacteria anaerobia Clostridium botulinum (NTBo). Bloquea la transmisión neuromuscular por lo cual es utilizada para el tratamiento de enfermedades con hiperactividad muscular, bloqueando la liberación de acetilcolina y así la transmisión sináptica en la unión neuromuscular, lo que lleva al debilitamiento y atrofia de los músculos. Este mecanismo de acción motivó el uso de la toxina botulínica en las enfermedades con elevado tono muscular, como la distonía y la espasticidad, por lo cual también ha revolucionado la opción de tratamiento de los trastornos autónomos de hipersecreción. La sialorrea es un síntoma común en diversas enfermedades neurológicas. Las inyecciones de toxina botulínica, guiadas por ultrasonidos en las glándulas salivales, produce una disminución de la salivación excesiva en niños con deficiencias neurológicas como parálisis cerebral. La utilización de la toxina botulínica tipo A ha sido sugerida como tratamiento de la sialorrea en pacientes con parálisis cerebral (PC). Esta recomendación ha sido hecha por el efecto anticolinérgico de esta sustancia, principalmente por su capacidad para bloquear la liberación de acetilcolina a nivel de las membranas pre-sinápticas Aunque la respuesta al tratamrento es distinta en cada niño, en general se ha observado que cuanto más a menudo se utiliza la toxlna botulínica y más alta es la dosis utilizada, los resultados son mejores. Los expertos consideran conveniente el procedimiento porque muchos de estos pacientes están utilizando la toxina botulínica para sus problemas musculares y las distrntas condiciones pueden ser tratadas al mismo tiempo Se reporta la descripción de la aplicación de toxina botulínica en una paciente niña que concurre al Instituto de Rehabilitación Infantil TELETON de la ciudad de Valparaíso, Chile, con un trastorno motor severo y con salivación incontrolada persistente que provoca enfermedades respiratorias a repetición

Bile Acids Induce Glucagon-Like Peptide 2 Secretion with Limited Effects on Intestinal Adaptation in Early Weaned Pigs

Early weaning is a stressful event characterized by a transient period of intestinal atrophy that may be mediated by reduced secretion of glucagon-like peptide (GLP) 2. We tested whether enterally fed bile acids or plant sterols could increase nutrient-dependent GLP-2 secretion and improve intestinal adaptation in weanling pigs. During the first 6 d after weaning, piglets were intragastrically infused once daily with either deionized water -control-, chenodeoxycholic acid -CDC; 60mg/kg body weight-, or b-sitoesterol -BSE; 100 mg/kg body weight-. Infusing CDC increased plasma GLP-2 -P menor que 0.05- but did not affect plasma GLP-1 and feed intake. The intestinal expression of Glp2r -glucagon-like peptide 2 receptor-, Asbt -sodium-dependent bile acid transporter-, Fxr -farnesoid X receptor-, and Tgr5 -guanosine protein?coupled bile acid receptor- genes were not affected by CDC treatment. The intragastric administration of CDC did not alter the weight and length of the intestine, yet increased the activation of caspase-3 in ileal villi -P menor que 0.02- and the expression of Il6 -interleukin 6; P menor que 0.002- in the jejunum. In contrast, infusing BSE did not affect any of the variables that were measured. Our results show that the enteral administration of the bile acid CDC potentiates the nutrient-induced secretion of endogenous GLP-2 in early-weaned pigs. Bile acid?enhanced release of GLP-2, however, did not result in improved intestinal growth, morphology, or inflammation during the postweaning degenerative phase.

Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: Relevance to diseases of the nervous system

Many proteins contain reiterated glutamine residues, but polyglutamine of excessive length may result in human disease by conferring new properties on the protein containing it. One established property of a glutamine residue, depending on the nature of the flanking residues, is its ability to act as an amine acceptor in a transglutaminase-catalyzed reaction and to make a glutamyl–lysine cross-link with a neighboring polypeptide. To learn whether glutamine repeats can act as amine acceptors, we have made peptides with variable lengths of polyglutamine flanked by the adjacent amino acid residues in the proteins associated with spinocerebellar ataxia type 1 (SCA1), Machado–Joseph disease (SCA3), or dentato-rubral pallido-luysian atrophy (DRPLA) or those residues adjacent to the preferred cross-linking site of involucrin, or solely by arginine residues. The polyglutamine was found to confer excellent substrate properties on any soluble peptide; under optimal conditions, virtually all the glutamine residues acted as amine acceptors in the reaction with glycine ethyl-ester, and lengthening the sequence of polyglutamine increased the reactivity of each glutamine residue. In the presence of transglutaminase, peptides containing polyglutamine formed insoluble aggregates with the proteins of brain extracts and these aggregates contained glutamyl–lysine cross-links. Repeated glutamine residues exposed on the surface of a neuronal protein should form cross-linked aggregates in the presence of any transglutaminase activated by the presence of Ca2+.

Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes

Streptozotocin (STZ), a glucose analogue known to induce diabetes in experimental animals, causes DNA strand breaks and subsequent activation of poly(ADPribose) polymerase (Parp). Because Parp uses NAD as a substrate, extensive DNA damage will result in reduction of cellular NAD level. In fact, STZ induces NAD depletion and cell death in isolated pancreatic islets in vitro. Activation of Parp therefore is thought to play an important role in STZ-induced diabetes. In the present study, we established Parp-deficient (Parp−/−) mice by disrupting Parp exon 1 by using the homologous recombination technique. These mice were used to examine the possible involvement of Parp in STZ-induced β-cell damage in vivo. The wild-type (Parp+/+) mice showed significant increases in blood glucose concentration from 129 mg/dl to 218, 370, 477, and 452 mg/dl on experimental days 1, 7, 21, and 60, respectively, after a single injection of 180 mg STZ/kg body weight. In contrast, the concentration of blood glucose in Parp−/− mice remained normal up to day 7, slightly increased on day 21, but returned to normal levels on day 60. STZ injection caused extensive necrosis in the islets of Parp+/+ mice on day 1, with subsequent progressive islet atrophy and loss of functional β cells from day 7. In contrast, the extent of islet β-cell death and dysfunction was markedly less in Parp−/− mice. Our findings clearly implicate Parp activation in islet β-cell damage and glucose intolerance induced by STZ in vivo.

Measuring the thickness of the human cerebral cortex from magnetic resonance images

Accurate and automated methods for measuring the thickness of human cerebral cortex could provide powerful tools for diagnosing and studying a variety of neurodegenerative and psychiatric disorders. Manual methods for estimating cortical thickness from neuroimaging data are labor intensive, requiring several days of effort by a trained anatomist. Furthermore, the highly folded nature of the cortex is problematic for manual techniques, frequently resulting in measurement errors in regions in which the cortical surface is not perpendicular to any of the cardinal axes. As a consequence, it has been impractical to obtain accurate thickness estimates for the entire cortex in individual subjects, or group statistics for patient or control populations. Here, we present an automated method for accurately measuring the thickness of the cerebral cortex across the entire brain and for generating cross-subject statistics in a coordinate system based on cortical anatomy. The intersubject standard deviation of the thickness measures is shown to be less than 0.5 mm, implying the ability to detect focal atrophy in small populations or even individual subjects. The reliability and accuracy of this new method are assessed by within-subject test–retest studies, as well as by comparison of cross-subject regional thickness measures with published values.

Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress

We report that 9 d of uncontrolled experimental diabetes induced by streptozotocin (STZ) in rats is an endogenous chronic stressor that produces retraction and simplification of apical dendrites of hippocampal CA3 pyramidal neurons, an effect also observed in nondiabetic rats after 21 d of repeated restraint stress or chronic corticosterone (Cort) treatment. Diabetes also induces morphological changes in the presynaptic mossy fiber terminals (MFT) that form excitatory synaptic contacts with the proximal CA3 apical dendrites. One effect, synaptic vesicle depletion, occurs in diabetes as well as after repeated stress and Cort treatment. However, diabetes produced other MFT structural changes that differ qualitatively and quantitatively from other treatments. Furthermore, whereas 7 d of repeated stress was insufficient to produce dendritic or synaptic remodeling in nondiabetic rats, it potentiated both dendritic atrophy and MFT synaptic vesicle depletion in STZ rats. These changes occurred in concert with adrenal hypertrophy and elevated basal Cort release as well as hypersensitivity and defective shutoff of Cort secretion after stress. Thus, as an endogenous stressor, STZ diabetes not only accelerates the effects of exogenous stress to alter hippocampal morphology; it also produces structural changes that overlap only partially with those produced by stress and Cort in the nondiabetic state.

Survival motor neuron protein modulates neuron-specific apoptosis

Spinal muscular atrophy (SMA) is attributed to mutations in the SMN1 gene, leading to loss of spinal cord motor neurons. The neurotropic Sindbis virus vector system was used to investigate a role for the survival motor neuron (SMN) protein in regulating neuronal apoptosis. Here we show that SMN protects primary neurons and differentiated neuron-like stem cells, but not cultured cell lines from virus-induced apoptotic death. SMN also protects neurons in vivo and increases survival of virus-infected mice. SMN mutants (SMNΔ7 and SMN-Y272C) found in patients with SMA not only lack antiapoptotic activity but also are potently proapoptotic, causing increased neuronal apoptosis and animal mortality. Full-length SMN is proteolytically processed in brains undergoing apoptosis or after ischemic injury. Mutation of an Asp-252 of SMN abolished cleavage of SMN and increased the antiapoptotic function of full-length SMN in neurons. Taken together, deletions or mutations of the C terminus of SMN that result from proteolysis, splicing (SMNΔ7), or germ-line mutations (e.g., Y272C), produce a proapoptotic form of SMN that may contribute to neuronal death in SMA and perhaps other neurodegenerative disorders.