Data on the association between age at natural menopause and physical function in older women from the International Mobility in Aging Study (IMIAS).

Women experience worse physical function and greater physical decline than men at similar ages. These sex differences are heterogeneous across settings and plausibly linked to gender inequality, with evidence of increasing disadvantage for women in increasingly iniquitous societies. As described in "Age at natural menopause and physical function in older women from Albania, Brazil, Colombia and Canada: A life-course perspective" [Velez et al., 2019] we assessed the association between age at natural menopause (ANM) and objectives markers of physical function (i.e., gait speed and grip strength) in older women from the International Mobility in Aging Study (IMIAS). For all sites combined, women with ANM ≥55 had higher gait speed than those with ANM 50-54. Women with ANM <40 had significantly lower grip strength compared with all other groups. In this article, we describe the region-specific associations between ANM, gait speed, and grip strength in 775 women aged 65-74, from the Southeastern European site (Tirana, Albania), Latin American sites (Manizales, Colombia and Natal, Brazil), and Canadian sites (Kingston, Ontario and Saint-Hyacinthe, Quebec). In region-specific analyses, ANM was associated with grip strength in Albania and Latin America and with gait speed in Albania only. No associations were observed in Canada.

Age at natural menopause and physical function in older women from Albania, Brazil, Colombia and Canada: A life-course perspective.

OBJECTIVE: Grip strength and gait speed are objective measures of physical function, which in turn is an indicator of biological aging. We evaluate the association between age at natural menopause (ANM) and physical functioning in a sample of postmenopausal women drawn from the International Mobility in Aging Study (IMIAS). STUDY DESIGN: Retrospective cohort study of 775 women aged 65-74, from Albania, Brazil, Colombia and Canada, who had experienced natural menopause. MAIN OUTCOME MEASURES: Gait speed and grip strength were obtained following standardized protocols. The association between self-reported ANM (<40, 40-44, 45-49, 50-54 and ≥55) and gait speed (m/s) and grip strength (kg) was assessed by linear regression analyses adjusting for several life-course economic and reproductive exposures, height, BMI and smoking. RESULTS: Overall, women with ANM ≥ 55 had higher gait speed than those with ANM 50-54 (ß = 0.05; 95%CI: 0.01, 0.10). Women with ANM < 40 had significantly lower grip strength compared with all other groups (ß= -2.58; 95%CI: -4.43, -0.74). In region-specific analyses, ANM was associated with grip strength in Albania and Latin America and with gait speed in Albania only. No associations were observed in Canada. CONCLUSIONS: ANM is associated with markers of physical functioning. Differences across study sites suggest that women in socially disadvantaged areas may reach menopause with different physiological reserves than those from more advantaged settings, leading to greater losses in muscle strength in postmenopausal years. More work comparing distinct populations is needed to better understand the underlying mechanisms.

Development of lupus nephritis in a patient with previous scleroderma renal crisis.

We present a case of scleroderma overlap syndrome with systemic lupus erythematosus (SLE) including complications of both scleroderma renal crisis and lupus nephritis. Our patient was initially diagnosed with undifferentiated connective tissue disease in 1996. A diagnosis of scleroderma was made in 2010 after she developed scleroderma renal crisis. She remained stable until 2016, when she presented with Salmonella bacteremia, renal failure, nephrotic range proteinuria and microscopic hematuria. Laboratory findings were consistent lupus with positive ds-DNA, hypocomplementemia and repeat renal biopsy showed lupus nephritis.

Towards understanding and predicting suicidality in women: biomarkers and clinical risk assessment.

Women are under-represented in research on suicidality to date. Although women have a lower rate of suicide completion than men, due in part to the less-violent methods used, they have a higher rate of suicide attempts. Our group has previously identified genomic (blood gene expression biomarkers) and clinical information (apps) predictors for suicidality in men. We now describe pilot studies in women. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation (no SI) and high suicidal ideation (high SI) states (n=12 participants out of a cohort of 51 women psychiatric participants followed longitudinally, with diagnoses of bipolar disorder, depression, schizoaffective disorder and schizophrenia). We then used a Convergent Functional Genomics (CFG) approach to prioritize the candidate biomarkers identified in the discovery step by using all the prior evidence in the field. Next, we validated for suicidal behavior the top-ranked biomarkers for SI, in a demographically matched cohort of women suicide completers from the coroner's office (n=6), by assessing which markers were stepwise changed from no SI to high SI to suicide completers. We then tested the 50 biomarkers that survived Bonferroni correction in the validation step, as well as top increased and decreased biomarkers from the discovery and prioritization steps, in a completely independent test cohort of women psychiatric disorder participants for prediction of SI (n=33) and in a future follow-up cohort of psychiatric disorder participants for prediction of psychiatric hospitalizations due to suicidality (n=24). Additionally, we examined how two clinical instruments in the form of apps, Convergent Functional Information for Suicidality (CFI-S) and Simplified Affective State Scale (SASS), previously tested in men, perform in women. The top CFI-S item distinguishing high SI from no SI states was the chronic stress of social isolation. We then showed how the clinical information apps combined with the 50 validated biomarkers into a broad predictor (UP-Suicide), our apriori primary end point, predicts suicidality in women. UP-Suicide had a receiver-operating characteristic (ROC) area under the curve (AUC) of 82% for predicting SI and an AUC of 78% for predicting future hospitalizations for suicidality. Some of the individual components of the UP-Suicide showed even better results. SASS had an AUC of 81% for predicting SI, CFI-S had an AUC of 84% and the combination of the two apps had an AUC of 87%. The top biomarker from our sequential discovery, prioritization and validation steps, BCL2, predicted future hospitalizations due to suicidality with an AUC of 89%, and the panel of 50 validated biomarkers (BioM-50) predicted future hospitalizations due to suicidality with an AUC of 94%. The best overall single blood biomarker for predictions was PIK3C3 with an AUC of 65% for SI and an AUC of 90% for future hospitalizations. Finally, we sought to understand the biology of the biomarkers. BCL2 and GSK3B, the top CFG scoring validated biomarkers, as well as PIK3C3, have anti-apoptotic and neurotrophic effects, are decreased in expression in suicidality and are known targets of the anti-suicidal mood stabilizer drug lithium, which increases their expression and/or activity. Circadian clock genes were overrepresented among the top markers. Notably, PER1, increased in expression in suicidality, had an AUC of 84% for predicting future hospitalizations, and CSNK1A1, decreased in expression, had an AUC of 96% for predicting future hospitalizations. Circadian clock abnormalities are related to mood disorder, and sleep abnormalities have been implicated in suicide. Docosahexaenoic acid signaling was one of the top biological pathways overrepresented in validated biomarkers, which is of interest given the potential therapeutic and prophylactic benefits of omega-3 fatty acids. Some of the top biomarkers from the current work in women showed co-directionality of change in expression with our previous work in men, whereas others had changes in opposite directions, underlying the issue of biological context and differences in suicidality between the two genders. With this study, we begin to shed much needed light in the area of female suicidality, identify useful objective predictors and help understand gender commonalities and differences. During the conduct of the study, one participant committed suicide. In retrospect, when the analyses were completed, her UP-Suicide risk prediction score was at the 100 percentile of all participants tested.

Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach.

Worldwide, one person dies every 40 seconds by suicide, a potentially preventable tragedy. A limiting step in our ability to intervene is the lack of objective, reliable predictors. We have previously provided proof of principle for the use of blood gene expression biomarkers to predict future hospitalizations due to suicidality, in male bipolar disorder participants. We now generalize the discovery, prioritization, validation, and testing of such markers across major psychiatric disorders (bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) in male participants, to understand commonalities and differences. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation and high suicidal ideation states (n=37 participants out of a cohort of 217 psychiatric participants followed longitudinally). We then used a convergent functional genomics (CFG) approach with existing prior evidence in the field to prioritize the candidate biomarkers identified in the discovery step. Next, we validated the top biomarkers from the prioritization step for relevance to suicidal behavior, in a demographically matched cohort of suicide completers from the coroner's office (n=26). The biomarkers for suicidal ideation only are enriched for genes involved in neuronal connectivity and schizophrenia, the biomarkers also validated for suicidal behavior are enriched for genes involved in neuronal activity and mood. The 76 biomarkers that survived Bonferroni correction after validation for suicidal behavior map to biological pathways involved in immune and inflammatory response, mTOR signaling and growth factor regulation. mTOR signaling is necessary for the effects of the rapid-acting antidepressant agent ketamine, providing a novel biological rationale for its possible use in treating acute suicidality. Similarly, MAOB, a target of antidepressant inhibitors, was one of the increased biomarkers for suicidality. We also identified other potential therapeutic targets or biomarkers for drugs known to mitigate suicidality, such as omega-3 fatty acids, lithium and clozapine. Overall, 14% of the top candidate biomarkers also had evidence for involvement in psychological stress response, and 19% for involvement in programmed cell death/cellular suicide (apoptosis). It may be that in the face of adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and organismal level. Finally, we tested the top increased and decreased biomarkers from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C), prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely independent test cohort of psychiatric participants for prediction of suicidal ideation (n=108), and in a future follow-up cohort of psychiatric participants (n=157) for prediction of psychiatric hospitalizations due to suicidality. The best individual biomarker across psychiatric diagnoses for predicting suicidal ideation was SLC4A4, with a receiver operating characteristic (ROC) area under the curve (AUC) of 72%. For bipolar disorder in particular, SLC4A4 predicted suicidal ideation with an AUC of 93%, and future hospitalizations with an AUC of 70%. SLC4A4 is involved in brain extracellular space pH regulation. Brain pH has been implicated in the pathophysiology of acute panic attacks. We also describe two new clinical information apps, one for affective state (simplified affective state scale, SASS) and one for suicide risk factors (Convergent Functional Information for Suicide, CFI-S), and how well they predict suicidal ideation across psychiatric diagnoses (AUC of 85% for SASS, AUC of 89% for CFI-S). We hypothesized a priori, based on our previous work, that the integration of the top biomarkers and the clinical information into a universal predictive measure (UP-Suicide) would show broad-spectrum predictive ability across psychiatric diagnoses. Indeed, the UP-Suicide was able to predict suicidal ideation across psychiatric diagnoses with an AUC of 92%. For bipolar disorder, it predicted suicidal ideation with an AUC of 98%, and future hospitalizations with an AUC of 94%. Of note, both types of tests we developed (blood biomarkers and clinical information apps) do not require asking the individual assessed if they have thoughts of suicide, as individuals who are truly suicidal often do not share that information with clinicians. We propose that the widespread use of such risk prediction tests as part of routine or targeted healthcare assessments will lead to early disease interception followed by preventive lifestyle modifications and proactive treatment.

Management of penoscrotal extramammary Paget disease: case series and review of the literature.

Extramammary Paget disease (empd) is a rare, slow-growing neoplasm, considered to be an adenocarcinoma of the apocrine glands. In men, the penoscrotal region is the most commonly affected area. The disease can present as carcinoma in situ or as invasive disease that can subsequently metastasize to lymph nodes and distant sites. Because of the rarity of empd, the medical literature available to guide management of the disease is limited, particularly in patients with metastases. In addition, metastatic disease may pose a diagnostic challenge, because invasive cancer of the genitourinary or gastrointestinal tract can occur in association with empd. In the present case series, we describe our experience in treating penoscrotal empd with multimodality therapy, and we review the existing literature concerning its diagnosis and management.

Chronic perfusion of angiotensin II causes cognitive dysfunctions and anxiety in mice.

High blood pressure is a major risk factor in the onset of cerebrovascular diseases and cognitive impairment. However, mechanisms by which these occur remain unclear and treatments are, therefore, ineffective to prevent cognitive decline related to cardiovascular diseases. Angiotensin II is a peptide involved in the onset and maintenance of hypertension and its effect on cognition was studied acutely but never chronically. Hence, the aim of this study is to evaluate whether chronic hypertensive levels of angiotensin II infusion alter cognitive functions in C57BL6 mice. In this study we used subcutaneous mini-pumps containing a concentration of angiotensin II (1900 ng/kg/min) that induces malignant hypertension or a saline solution for 14 and 21 days. Blood pressure was carefully monitored by a non-invasive tail-cuff method every week throughout the experiment. Spatial memory was assessed using the Morris water maze test and anxiety was measured by the elevated plus maze and the open field tests. The results indicate learning and spatial memory deficit as well as an anxious behavior induced by angiotensin II, in comparison to the vehicle group, starting at the 3rd week of perfusion. The motricity and visual acuity were equivalent in angiotensin II perfused mice compared to their respective control. These results suggest a strong relationship between angiotensin II and the development of cognitive dysfunctions and anxiety along with sustained high blood pressure.

In vivo evaluation of demyelination and remyelination in a nerve crush injury model.

Nerves of the peripheral nervous system have, to some extent, the ability to regenerate after injury, particularly in instances of crush or contusion injuries. After a controlled crush injury of the rat sciatic nerve, demyelination and remyelination are followed with functional assessments and imaged both ex vivo and in vivo over the course of 4 weeks with video-rate coherent anti-Stokes Raman scattering (CARS) microscopy. A new procedure compatible with live animal imaging is developed for performing histomorphometry of myelinated axons. This allows quantification of demyelination proximal and remyelination distal to the crush site ex vivo and in vivo respectively.

Dismantling of Arabidopsis thaliana mesophyll cell chloroplasts during natural leaf senescence.

One of the earliest events in the process of leaf senescence is dismantling of chloroplasts. Mesophyll cell chloroplasts from rosette leaves were studied in Arabidopsis thaliana undergoing natural senescence. The number of chloroplasts decreased by only 17% in fully yellow leaves, and chloroplasts were found to undergo progressive photosynthetic and ultrastructural changes as senescence proceeded. In ultrastructural studies, an intact tonoplast could not be visualized, thus, a 35S-GFP::delta-TIP line with a GFP-labeled tonoplast was used to demonstrate that chloroplasts remain outside of the tonoplast even at late stages of senescence. Chloroplast DNA was measured by real-time PCR at four different chloroplast loci, and a fourfold decrease in chloroplast DNA per chloroplast was noted in yellow senescent leaves when compared to green leaves from plants of the same age. Although chloroplast DNA did decrease, the chloroplast/nuclear gene copy ratio was still 31:1 in yellow leaves. Interestingly, mRNA levels for the four loci differed: psbA and ndhB mRNAs remained abundant late into senescence, while rpoC1 and rbcL mRNAs decreased in parallel to chloroplast DNA. Together, these data demonstrate that, during senescence, chloroplasts remain outside of the vacuole as distinct organelles while the thylakoid membranes are dismantled internally. As thylakoids were dismantled, Rubisco large subunit, Lhcb1, and chloroplast DNA levels declined, but variable levels of mRNA persisted.

Quantitative myelin imaging with coherent anti-Stokes Raman scattering microscopy: alleviating the excitation polarization dependence with circularly polarized laser beams.

The use of coherent anti-Stokes Raman scattering microscopy tuned to the lipid vibration for quantitative myelin imaging suffers from the excitation polarization dependence of this third-order nonlinear optical effect. The contrast obtained depends on the orientation of the myelin membrane, which in turn affects the morphometric parameters that can be extracted with image analysis. We show how circularly polarized laser beams can be used to avoid this complication, leading to images free of excitation polarization dependence. The technique promises to be optimal for in vivo imaging and the resulting images can be used for coherent anti-Stokes Raman scattering optical histology on native state tissue.

Purely axial compression of fiber Bragg gratings embedded in a highly deformable polymer.

We demonstrate a tuning device for fiber Bragg gratings with a wavelength tuning range in excess of 65 nm. A purely axial tuning technique using a highly deformable polymer molded in a cylinder shape is used to embed a fiber Bragg grating and to achieve a wavelength tuning range from 1551.7 to 1485.5 nm. The tuning curve is highly linear with a tuning rate of 9.6 nm for every percent of applied strain. The insertion losses of the device, the variations of the full width at half maximum, and the stability of the Bragg wavelength over a working day have been studied and shown to be less than 0.02 dB, 0.14, and 0.2 nm, respectively.

Progesterone receptor reactivity in renal oncocytoma and chromophobe renal cell carcinoma.

AIMS: To investigate the reactivity for oestrogen and progesterone receptors (ER and PR) in renal oncocytoma (RO) and chromophobe renal cell carcinoma (CHRCC). MATERIALS AND METHODS: Thirty-eight RO, 25 CHRCC, 20 papillary RCC with oncocytic cytoplasm and 10 clear cell RCC with dominant eosinophilic cytoplasm were submitted for immunohistochemistry for ER, PR, CD117 and RCC. RESULTS: All cases of RO and CHRCC displayed moderately positive reactivity for PR. The nuclear reactivity ranged from 60% to 90% in RO and from occasional cells to 70% in CHRCC. In CHRCC, reactivity tended to be more prevalent in areas of tumour cells with eosinophilic cytoplasm. Progesterone reactivity was focal in areas. All RO and most CHRCC were reactive for CD117 and neither RO nor CHRCC was reactive for RCC. CD117 reactivity tended to be more intense in CHRCC than in RO. Negative reactivity for CD117 and positive reactivity for RCC were observed in almost all RCC, as reported in the literature. CONCLUSIONS: PR can be used in combination with CD117 and RCC in the differential diagnosis of RO and eosinophilic variant of CHRCC with other RCC with oncocytic or eosinophilic cytoplasm.

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions.

Myotonic dystrophy (DM1) is caused by the expansion of a trinucleotide repeat (CTG) located in the 3'untranslated region of the myotonic dystrophy protein kinase gene, for which currently there is no effective treatment. The data available suggest that misregulation of RNA homeostasis may play a major role in DM1 muscle pathogenesis. This indicates that the specific targeting of the mutant DMPK transcripts is essential to raise the rationale basis for the development of a specific gene therapy for DM1. We have produced a retrovirus which expresses a 149-bp antisense RNA complementary to the (CUG)13 repeats and to the 110-bp region following the repeats sequence to increase the specificity. This construct was introduced into human DM1 myoblasts, resulting in a preferential decrease in mutant DMPK transcripts, and effective restoration of human DM1 myoblast functions such as myoblast fusion and the uptake of glucose. It was previously shown that delay of muscle differentiation and insulin resistance in DM1 are associated with misregulation of CUGBP1 protein levels. The analysis of CUGBP1 levels and activity in DM1 cells expressing the antisense RNA indicated a correction of CUGBP1 expression in infected DM1 cells. We therefore show that current antisense RNA delivered in vitro using a retrovirus is not only capable of inhibiting mutant DMPK transcripts, but also can ameliorate dystrophic muscle pathology at the cellular levels.

Unusual methyl-branched alpha,beta-unsaturated acyl chain substitutions in the Nod Factors of an arctic rhizobium, Mesorhizobium sp. strain N33 (Oxytropis arctobia).

Mesorhizobium sp. strain N33 (Oxytropis arctobia), a rhizobial strain isolated in arctic Canada, is able to fix nitrogen at very low temperatures in association with a few arctic legume species belonging to the genera Astragalus, Onobrychis, and Oxytropis. Using mass spectrometry and nuclear magnetic resonance spectroscopy, we have determined the structure of N33 Nod factors, which are major determinants of nodulation. They are pentameric lipochito-oligosaccharides 6-O sulfated at the reducing end and exhibit other original substitutions: 6-O acetylation of the glucosamine residue next to the nonreducing terminal glucosamine and N acylation of the nonreducing terminal glucosamine by methyl-branched acyl chains of the iso series, some of which are alpha,beta unsaturated. These unusual substitutions may contribute to the peculiar host range of N33. Analysis of N33 whole-cell fatty acids indicated that synthesis of the methyl-branched fatty acids depended on the induction of bacteria by plant flavonoids, suggesting a specific role for these fatty acids in the signaling process between the plant and the bacteria. Synthesis of the methyl-branched alpha,beta-unsaturated fatty acids required a functional nodE gene.

Structure and promoter activity of the mouse CDC25A gene.

CDC25A is a member of a group of highly related, dual-specificity phosphatases that promote cell cycle phase transitions by regulating the activity of cyclin-dependent kinases. Here we report the cloning and genomic sequence of 21,067 nucleotides encompassing the mouse CDC25A gene. The coding sequence is expressed from 17,904 bp of genomic DNA comprising 15 exons. We also mapped the transcription initiation site to a consensus initiator element proximal to an SP1 site. Approximately 1 kb of sequence upstream of the transcription initiation site confers promoter activity and cell type specificity to a reporter gene construct. Surprisingly, transcription from this promoter was repressed by over-expression of catalytically active but not catalytically inactive CDC25A protein. We also show, using NIH 3T3 cells, that murine CDC25A mRNA levels fluctuate only modestly over the cell cycle. Our findings provide insights into the regulation of CDC25A expression and have facilitated construction of gene knock-out vectors.

Tuberculosis of the axis in a patient with systemic sarcoidosis: technique of posterior open biopsy of the dens: case report.

OBJECTIVE AND IMPORTANCE: This case report illustrates the importance of obtaining tissue from a destructive lesion of the dens in a patient with systemic sarcoidosis. Although sarcoidosis can involve the axial skeleton, tissue obtained at the time of C1-C2 fusion demonstrated unsuspected pathological features, which dramatically altered the subsequent medical treatment. The technique of open posterior biopsy of the dens is illustrated, and the advantages of the approach are discussed. CLINICAL PRESENTATION: A 40-year-old woman with systemic sarcoidosis developed neck pain and atlantoaxial instability. Imaging revealed multiple thoracic and cervical vertebral abnormalities, including a destructive enhancing lesion involving the base of the dens. INTERVENTION: At the time of posterior C1-C2 fusion, we elected to perform an open biopsy of the base of the dens. A 16-gauge biopsy needle was introduced along the medial portion of the left C2 pars, aiming medially toward the base of the odontoid process. This procedure was performed under direct observation, with fluoroscopic guidance. The biopsy specimen contained caseating granulomas, and cultures were positive for Mycobacterium tuberculosis. CONCLUSION: The unusual presentation, the technique, and the importance of obtaining tissue to confirm the diagnosis of tuberculous involvement of the dens are emphasized. The relationship between sarcoidosis and tuberculosis reported in the literature is reviewed. In the current case, cell wall-positive tuberculous bacteria were cultured, confirming the presence of two separate diseases in the same patient.

Subacute posttraumatic ascending myelopathy after spinal cord injury. Report of three cases.

Subacute posttraumatic ascending myelopathy is a rare disorder, unrelated to syrinx formation or mechanical instability, that may gradually emerge within the first 1 to 2 weeks after a spinal cord injury. The authors describe three patients with this syndrome and discuss its possible causes as well as its clinical presentation, imaging characteristics, treatment, and patient prognosis.