Testosterone effect on brain metabolism in elderly patients with Alzheimer's disease: comparing two cases at different disease stages.

OBJECTIVE: To describe the effect of testosterone replacement therapy (TRT) on the brain activity of two demented, hypogonadal male patients with early and late-stage Alzheimer's disease (AD), respectively. METHODS: We describe the clinical and positron emission tomography (PET) findings for two individuals, one with early stage and the other with late-stage Alzheimer's disease, before and after treatment with a topical testosterone gel. Both patients were hypogonadal at baseline. We assessed cerebral glucose metabolism (CGM) via (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). We investigated whether there are testosterone-susceptible areas within cerebral structures in patients with Alzheimer's disease. RESULTS: Under testosterone replacement therapy, changes in cerebral glucose metabolism were observed in both patients. Improvement in glucose uptake was observed most consistently in the parietal lobe and brainstem; decreased glucose metabolism was observed in the temporal lobe, the limbic system and the insula for these two subjects. DISCUSSION: These case reports demonstrate the potential for PET scanning to detect changes in cerebral glucose metabolism in hypogonadal men with Alzheimer's disease who are treated with testosterone. Further study will be needed to investigate the consistency and significance of these changes in terms of magnitude and brain region, and the correlation with functional changes.

Impact of surgical ventricular restoration on ventricular shape, wall stress, and function in heart failure patients.

Surgical ventricular restoration (SVR) was designed to treat patients with aneurysms or large akinetic walls and dilated ventricles. Yet, crucial aspects essential to the efficacy of this procedure like optimal shape and size of the left ventricle (LV) are still debatable. The objective of this study is to quantify the efficacy of SVR based on LV regional shape in terms of curvedness, wall stress, and ventricular systolic function. A total of 40 patients underwent magnetic resonance imaging (MRI) before and after SVR. Both short-axis and long-axis MRI were used to reconstruct end-diastolic and end-systolic three-dimensional LV geometry. The regional shape in terms of surface curvedness, wall thickness, and wall stress indexes were determined for the entire LV. The infarct, border, and remote zones were defined in terms of end-diastolic wall thickness. The LV global systolic function in terms of global ejection fraction, the ratio between stroke work (SW) and end-diastolic volume (SW/EDV), the maximal rate of change of pressure-normalized stress (dσ*/dt(max)), and the regional function in terms of surface area change were examined. The LV end-diastolic and end-systolic volumes were significantly reduced, and global systolic function was improved in ejection fraction, SW/EDV, and dσ*/dt(max). In addition, the end-diastolic and end-systolic stresses in all zones were reduced. Although there was a slight increase in regional curvedness and surface area change in each zone, the change was not significant. Also, while SVR reduced LV wall stress with increased global LV systolic function, regional LV shape and function did not significantly improve.

Revisiting the effect of referral bias on the clinical spectrum of infective endocarditis in adults.

Referral bias occurs because of the clustering of patients at tertiary care centers. This may result in the distortion of observed clinical manifestations of rare diseases. This analysis evaluates the effect of referral bias on the epidemiology of infective endocarditis (IE) in the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS). This is a prospective multicenter cohort study comparing transferred and non-transferred patients with IE. Factors independently associated with transfer status were evaluated using multivariable logistic regression. A total of 2,760 patients were included in the analysis, of which 1,164 (42.2%) were transferred from other medical centers. Transferred patients more often underwent surgery for IE (odds ratio [OR] = 2.5; 95% confidence interval [CI] 1.9-3.2). They were also more likely to have complications such as stroke (OR = 1.5; 95% CI 1.3-1.9), heart failure (OR = 1.4; 95% CI 1.1-1.6), and new valvular regurgitation (OR = 1.3; 95% CI 1.1-1.6). The in-hospital mortality rates were similar in both groups. Patients with IE who require surgery and suffer complications are referred to tertiary hospitals more frequently than patients with an uncomplicated course. Hospital transfer has no obvious effect on the in-hospital mortality. Referral bias should be taken into consideration when describing the clinical spectrum of IE.

Diagnostic and Predictive Applications of Functional Near-Infrared Spectroscopy for Major Depressive Disorder: A Systematic Review.

INTRODUCTION: Major depressive disorder (MDD) is a global psychiatric disorder with no established biomarker. There is growing evidence that functional near-infrared spectroscopy (fNIRS) has the ability to aid in the diagnosis and prediction of the treatment response of MDD. The aim of this review was to systematically review, and gather the evidence from existing studies that used fNIRS signals in the diagnosis of MDD, correlations with depression symptomatology, and the monitoring of treatment response. METHODS: PubMed, EMBASE, ScienceDirect, and Cochrane Library databases were searched for published English articles from 1980 to June 2019 that focused on the application of fNIRS for (i) differentiating depressed versus nondepressed individuals, (ii) correlating with depression symptomatology, and in turn (iii) monitoring treatment responses in depression. Studies were included if they utilized fNIRS to evaluate cerebral hemodynamic variations in patients with MDD of any age group. The quality of the evidence was assessed using the Newcastle-Ottawa quality assessment scale. RESULTS: A total of 64 studies were included in this review, with 12 studies being longitudinal, while the rest were cross-sectional. More than two-thirds of the studies (n = 49) had acceptable quality. fNIRS consistently demonstrated attenuated cerebral hemodynamic changes in depressed compared to healthy individuals. fNIRS signals have also shown promise in correlating with individual symptoms of depression and monitoring various treatment responses. CONCLUSIONS: This review provides comprehensive updated evidence of the diagnostic and predictive applications of fNIRS in patients with MDD. Future studies involving larger sample sizes, standardized methodology, examination of more brain regions in an integrative approach, and longitudinal follow-ups are needed.

An unusual case of vascular hypogonadism treated with clomiphene citrate and testosterone replacement.

Many male patients are discovered on screening to suffer from hypogonadism and age related hypogonadism is being increasingly recognized. However, secondary causes of hypogonadism should not be overlooked, especially in patients who may have concomitant morbidity as highlighted in this case. Our patient with vascular hypogonadism was treated with testosterone and clomiphene citrate in cycles; with a hope of improving not only androgen levels but overall pituitary function as there were co-existing endocrine pathologies of albeit primary hypothyroidism and low IGF-1 levels. Treatment with exogenous testosterone is fairly well established; but there is also increasing evidence of the effectiveness and short-term safety of clomiphene citrate in restoring not only biological levels but functional states in males as well. As such, we report an unusual case of a patient seen at our Men's Health & Andrology clinic in which both the cause of some otherwise unremarkable symptoms and the treatment, using a combination of clomiphene citrate and testosterone, were remarkable.

Preference for gender of health care provider in management of erectile dysfunction.

We investigated whether a preference by patients regarding the gender of a health care provider to manage erectile dysfunction (ED) may be a factor in the diagnosis and care of this condition, whose broader medical significance is an area of increasing interest. A brief questionnaire was completed by 1087 adult males in a primary care setting. The questionnaire explored provider gender preference and other possible biases. The prevalence of ED in the 40-69 age group in our population was 68.8%. The prevalence was 81% in the age group of 70 and more. Of those who reported having experienced ED, 51.5% had discussed it with a provider, and 28.1% had been treated. Approximately, 57% expressed no provider gender preference, regardless of history of ED. Of those who stated a preference, approximately 75% prefer male providers. However, also among those who state a preference, Hispanics are not as likely as non-Hispanics to prefer a male provider (P=0.03). Most believe that males and females are equally qualified to manage ED, but among those who have a different opinion, the gender perceived more favorably is male. The issue of privacy during the discussion of ED was also very important to the respondents in this study.

Stenosis detection and quantification on cardiac CTCA using panoramic MIP of coronary arteries.

In this work, we proposed to demonstrate the entire 3D coronary tree using panoramic maximum intensity projection (MIP) of coronary arteries, and to detect and quantify coronary stenosis from computed tomography coronary angiography (CTCA). The performance of the proposed method was assessed in comparison with invasive coronary angiography (ICA) as reference standard. Six anonymized CTCA datasets were tested. MIP method achieved a sensitivity of 82% and a specificity of 95% for the stenosis detection with a good reproducibility (i.e. Cohen's kappa coefficient of 0.74 for the intra-rater agreement, and 0.45 for the inter-raters agreement). In stenosis quantification, three image options are provided. The original density images resulted in an accuracy of 0.85. The edge map images resulted in an accuracy of 0.79. The image combination had a better accuracy of 0.89 than any single image option. In conclusion, the panoramic MIP provided fast and accurate way for the stenosis detection and quantification. It may be helpful to assist the radiologist in identifying the location of the greatest narrowing in clinical practice.

Identification of the lysyl oxidase gene as target of the antioncogenic transcription factor, IRF-1, and its possible role in tumor suppression.

The transcriptional activator IFN regulatory factor 1 (IRF-1) and its antagonistic repressor IRF-2 are regulators of the IFN system. IRF-1 also manifests tumor suppressive activity, and its inactivation could contribute to the development of human hematopoietic malignancies. Here, we report the identification of the lysyl oxidase gene as a target gene of IRF-1. An IRF response element was identified in the lysyl oxidase gene promoter. We also demonstrate that the transformed phenotype of ras-expressing embryonic fibroblasts with a null mutation in the IRF-1 allele could be suppressed by the expression of the lysyl oxidase cDNA, implicating its potential role in tumor suppression. Thus, the regulation of the lysyl oxidase gene by IRF-1 could contribute to the multistep process of malignant transformation.

Biological and biochemical effects of 2'-azido-2'-deoxyarabinofuranosylcytosine on human tumor cells in vitro.

2-azido-2'-deoxyarabinofuranosylcytosine (Cytarazid), recently synthesized, was found to inhibit the in vitro growth of several human cell lines by 50% at concentrations ranging from 0.06 to 0.2 microM and to prevent the replication of herpes simplex virus types 1 and 2 by 98% at 50 microM. As determined with HeLa cells, the inhibition of cell growth was partially prevented by 2'-deoxycytidine (dCyd) and cytidine but not by uridine or thymidine. Cytarazid proved resistant to deamination by human cytidine/dCyd deaminases purified from acute myelocytic leukemia blast cells and from liver, a property reflected in the inability of tetrahydrouridine to enhance the cytotoxicity of the compound. Cytarazid served as a substrate for cytoplasmic dCyd kinase partially purified from human peripheral chronic lymphocytic leukemia blast cells. At a concentration of 0.4 mM, the nucleoside analog was phosphorylated 2.6 times more effectively by this enzyme than was dCyd, the Km for Cytarazid being 250 microM. In intact HeLa cells, the triphosphate derivative of Cytarazid was the major drug metabolite formed. In these cells, the analog interfered with the incorporation of radiolabeled thymidine into DNA at a concentration and a time interval at which the incorporation of uridine into RNA and amino acids into protein was not inhibited, suggesting that interference with DNA synthesis is a primary drug effect. Further analysis showed that Cytarazid triphosphate interferes with DNA synthesis in intact HeLa cell nuclei and that it inhibits both the alpha- and beta-DNA polymerases purified from HeLa cells in a manner competitive with deoxycytidine triphosphate, with Ki's of 0.6 and 0.7 microM, respectively. Cytarazid triphosphate was not able to replace deoxycytidine triphosphate for the synthesis of DNA in either intact nuclei or in cell-free preparations; but, in the cell-free assay system, the compound was found to interfere with primer-template activity.

Demonstration of Epstein-Barr virus-specific DNA polymerase in chemically induced Raji cells and its antibody in serum from patients with nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) has been found to be associated with nasopharyngeal carcinoma (NPC), and antibodies with high frequency and titer to EBV proteins have been found in sera from NPC patients. Raji cells, an EBV genome-carrying nonproducer cell line, treated with 12-O-tetradecanoylphorbol-13-acetate and n-butyrate induced a unique EBV DNA polymerase which has properties similar to the EBV DNA polymerase induced by 12-O-tetradecanoylphorbol-13-acetate in P3HR-1 cells, an EBV producer cell line. The possible presence of antibodies to this EBV DNA polymerase in NPC patient serum was examined. The mean number of EBV DNA polymerase units neutralized was 380 +/- 168 units/ml serum (mean +/- SD) in 48 sera from patients with NPC, whereas that in the sera from 52 healthy donors was 62 +/- 56 units/ml (p less than 0.01). The EBV DNA polymerase antibody was found to be associated with the immunoglobulin G but not the immunoglobulin A fraction, and its titer was not correlated with the titers against EBV DNase or virus capsid antigen-immunoglobulin A. Whether the EBV DNA polymerase antibody is against the EBV DNA polymerase core protein or its stimulating protein is still being investigated. This study demonstrated the high frequency and high titer of antibody against EBV DNA polymerase in serum from NPC patients and suggested the potential of utilizing this antibody titer to complement other methods for the early diagnosis or prognosis of NPC.

Induction of virus enzymes by phorbol esters and n-butyrate in Epstein-Barr virus genome-carrying Raji cells.

Phorbol esters and n-butyrate (SB) together could induce Epstein-Barr virus (EBV) DNA polymerase and DNase activities in Raji cells (virus nonproducer). Neither 12-O-tetradecanoylphorbol-13-acetate (TPA) nor SB alone could induce these EBV enzyme activities, transcription of the EcoRI C-region or other EBV proteins in Raji cells. The enzyme induction caused by exposure of Raji cells to TPA-SB was the result of the synthesis of virus-specified RNA, and the increase of linear EBV DNA content in Raji cells caused by TPA alone was not sufficient for induction of EBV-enzyme activities. Temporal characteristics of the TPA-SB induction process, but not the phorbol 12,13-dibutyrate-SB induction process, in Raji cells were observed; a critical phase (10-24 h) postphorbol ester treatment in phorbol 12,13-dibutyrate-SB-treated Raji cells which was responsible for the synthesis of virus RNA and enzymes was found. Phospholipase C, which increases intracellular diacylglycerols (and subsequently activates protein kinase C) was able to partially substitute for TPA in the TPA-SB induction for EBV polymerase and DNase activities. Sphingosine, a protein kinase C inhibitor, partially prevented the induction of virus enzyme activities in Raji cells treated with phorbol 12,13-dibutyrate and SB. No apparent changes in the methylation state of EBV DNA (EcoRI C region) were observed when Raji cells were treated with SB and TPA, alone or in combination. These results suggest that induction of EBV polymerase and DNase activities by TPA-SB may involve protein kinase C activation and another factor triggered by SB which together increase transcription of EBV DNA.

Alteration of the pharmacokinetics of high-dose ara-C by its metabolite, high ara-U in patients with acute leukemia.

The pharmacokinetics of high-dose cytosine arabinoside (HiDAC) given as a three-hour intravenous infusion at 3 g/m2 were studied in five patients with acute leukemia during relapse and/or remission of their disease. Apparent steady state plasma levels of ara-C during 13 infusions averaged 115 +/- 32 microM. Upon cessation of the infusion, cytosine arabinoside (ara-C) was rapidly cleared from the plasma. The apparent postinfusion kinetics of ara-C were triexponential with a distribution half-life of 16 minutes and elimination half-lives of 1.8 hours and six hours. Total clearance averaged 86 L per hour and mean residence time averaged 0.47 hours. Disease status (relapse or remission) had no apparent effect on the pharmacokinetic characteristics of ara-C. Peak levels of ara-U averaged 310 microM and the metabolite had an average apparent elimination half-life of 3.75 hours. Despite the persistence of ara-U at about 100 microM at the time of administration of subsequent infusions of ara-C, there was no further accumulation of ara-U in the plasma with repetitive infusions of HiDAC. In vitro studies indicate that ara-U can exert an inhibitory effect on deoxycytidine (dCyd) deaminase activity. The ratio of the Ki of ara-U to the Km of ara-C for cytidine (Cyd)-dCyd deaminase is 40:1; however, during the gamma phase of ara-C elimination, the ratio of ara-U:ara-C in plasma is at least 100:1. Thus, a retardation of systemic catabolism of ara-C by ara-U is possible. Two to three hours after the termination of the HiDAC infusion, the ara-C cerebrospinal fluid: plasma ratio is 1-3:1, a feature of potential therapeutic significance. The slower elimination of ara-C from the CSF may also contribute to the plasma gamma half-life.

Virus-induced thymidine kinases as markers for typing herpes simplex viruses and for drug sensitivity assays.

A rapid, reproducible and objective new method for typing herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) based on the effects of virus-induced thymidine kinases on various antiviral drugs has been developed. When several laboratory strains and clinical isolates were typed by this method and compared to the results obtained by the immunofluorescence antibody typing method, agreement was found for all the viruses. The new technique has the added advantage of determining the sensitivity of HSV strains to antiviral drugs.

Molecular analysis of hypoxanthine phosphoribosyl transferase mutants induced by glycidyl 1-naphthyl ether in mouse spleen cells in vivo.

Treatment of C57BL/6J mice with an epoxide, glycidyl 1-naphthyl ether (GNE), resulted in an average of a 3.4-fold increase in frequency of 6-thioguanine-resistant mutants of mouse spleen T-lymphocytes. In similar experiments with the epoxide trichloropropylene oxide, no increase in mutant frequency was found. To determine the kind and location of mutations in the coding region of the hypoxanthine phosphoribosyl transferase (HPRT) gene, 26 GNE-induced mutants and 17 spontaneous mutants were analyzed by direct sequencing of polymerase chain reaction amplified cDNA. Among the GNE-induced mutants, HPRT cDNA was present in 22, while that from 4 could not be detected. Among the spontaneous mutants, HPRT cDNA was present in 15 and absent in 2. Among GNE-induced mutants, base substitution in HPRT occurred in 15 of 22 mutants analyzed. Nine of 15 base substitutions involved TA base pairs, primarily TA-->CG transitions. Base substitutions were found throughout exons 3-7 but 46% of substitutions were located in exon 3 and one frameshift mutation involving a GC base pair in exon 3 was also observed. Among the spontaneous mutants, base substitutions of HPRT occurred in 7 of 15 mutants analyzed with 6 of 7 base substitutions involving a TA base pair and another 2 of the 15 mutants showed a 4 base pair deletion. The base substitution spectrum in GNE-induced mutants was different from that of the spontaneous mutants.

The Brugada syndrome in a Chinese population.

Sudden cardiac death has been reported in patients with a unique electrocardiographic (ECG) abnormality showing right bundle branch block and ST segment elevation in the precordial leads. This syndrome was first described by Brugada and Brugada and has not been previously described in a Chinese population. We report here the first three cases in Singapore. The first patient was a 49-year-old man who presented with syncope, associated with generalized convulsions. The second patient was a 25-year-old man who complained of palpitations but no syncope. The third patient was a 77-year-old man who presented with recurrent episodes of syncope and collapsed with ventricular fibrillation. All patients had no past cardiac or drug history of note. The neurological examination and investigations were normal. All three patients showed a unique right bundle branch block pattern with ST segment elevation in leads V1-3. The echocardiogram and 24-h ambulatory ECG monitoring, were normal. Single vessel disease was present in the third patient. Electrophysiological studies performed in all three patients were able to induce ventricular fibrillation. The patient with resuscitated cardiac death underwent an implantable cardioverter defibrillator implantation. The importance of this syndrome is that the recognition of the unique ECG pattern enables early identification and treatment of these patients.

The andropause and memory loss: is there a link between androgen decline and dementia in the aging male?

Studies demonstrate a decline in androgens with age and this results in the andropause. The objective of this paper is to review the literature on hormonal changes that occur in the aging males and determine if there are associations between decreased testosterone, dehydroepiandrosterone (DHEA) and decreased cognitive function. Trials of androgen replacement and its impact on cognitive function will also be analyzed. Method of analysis will be by a thorough search of articles on MEDLINE, the Internet and major abstract databases. Results of the author's own research in 302 men of the association of memory loss as a symptom in the andropause will be presented. In addition, the authors open trial of testosterone replacement in hypogonadic men with Alzheimer's disease will also be presented. The results of the author's trial will be compared with other investigators. High endogenous testosterone level predicted better performance on visual spatial tests in several studies, but not in all studies. Likewise, testosterone replacement in hypogonadic patients improved cognitive functions in some but not all studies. Testosterone has also been shown to improve cognitive function in eugonadal men. Several studies have shown that declines in DHEA may contribute to Alzheimer's disease and the results of double blind studies with DHEA replacement and its effect on cognition will also be presented. In summary, there is still no consensus that androgen replacement is beneficial in cognitive decline but this option may prove promising in some patients.

Role of androgens in mild cognitive impairment and possible interventions during andropause.

Mild cognitive impairment (MCI) is becoming fashionable as a diagnosis, representing a state of cognitive decline associated with negligible functional loss. MCI is important as it often precedes Alzheimer's disease (AD). Recognizing MCI may lead to preventive strategies that can delay the onset of AD. Many patients who transition into andropause report problems with their memory. There is strong evidence from basic sciences and epidemiological studies that both estrogens and androgens play a protective role in neurodegeneration. The evidence from small prospective clinical trials lends support to the role of hormones in improving cognitive function. The improvement in cognitive function with hormones is subtle and often not measurable on standard neuropsychological batteries. Patients have reported memory improvements in both declarative and procedural domains after being on hormonal replacement. Functional changes and vascular changes can be detected after hormonal replacement with more sophisticated imaging of the brain like PET scans. We hypothesize androgens and perhaps selective androgen receptor modulators as future treatment options for MCI in aging males.

Role of androgens in mild cognitive impairment and possible interventions during andropause.

Mild cognitive impairment (MCI) is becoming fashionable as a diagnosis, representing a state of cognitive decline associated with negligible functional loss. MCI is important as it often precedes Alzheimer's disease (AD). Recognizing MCI may lead to preventive strategies that can delay the onset of AD. Many patients who transition into andropause report problems with their memory. There is strong evidence from basic sciences and epidemiological studies that both estrogens and androgens play a protective role in neurodegeneration. The evidence from small prospective clinical trials lends support to the role of hormones in improving cognitive function. The improvement in cognitive function with hormones is subtle and often not measurable on standard neuropsychological batteries. Patients have reported memory improvements in both declarative and procedural domains after being on hormonal replacement. Functional changes and vascular changes can be detected after hormonal replacement with more sophisticated imaging of the brain like positron emission tomography (PET) scans. We hypothesize androgens and perhaps selective androgen receptor modulators as future treatment options for MCI in aging males.

Coronary artery disease: comprehensive evaluation by cardiovascular magnetic resonance imaging.

Cardiac magnetic resonance (CMR) imaging has emerged as an important non-invasive cardiac imaging modality. A versatile technique, it has the potential for comprehensive evaluation of coronary artery disease (CAD): cardiac morphology and function, myocardial perfusion, myocardial viability, coronary artery visualisation and atherosclerotic plaque characterisation. Some of these techniques--ventricular function and myocardial viability assessment--have already made mainstream clinical impact. Other techniques have yielded promising initial results, and will become increasingly accepted with technical refinement in scanner hardware and software. This article reviews the current status of clinical CMR imaging for diagnosis of CAD.

Goldberger's triad in dilated cardiomyopathy--can it predict the severity of left ventricular dysfunction?

Goldberger's triad is a specific, but relatively insensitive, electrocardiographic sign for dilated cardiomyopathy. To study the correlation between the presence of this sign and the severity of left ventricular dysfunction, the electrocardiograms and echocardiographically-determined left ventricular parameters of 17 patients (mean age 59.3 +/- 11.8 years) with dilated cardiomyopathy were examined. Five of the patients had Goldberger's triad. We found that the mean left atrial diameter, the mean left ventricular internal diameters (both end-systolic and end-diastolic) and the mean left ventricular ejection fraction of the group of patients with Goldberger's triad did not differ significantly from the group without. Coronary angiography revealed occult coronary artery disease in 5 of 12 patients. A larger, prospective study is required to verify our finding.