Male Andropause : A Myth or Reality

Male andropause, male climacteric or viropause is a condition in which men suffer from complex symptomatology due to low androgen level with aging. After the age of 40 years testosterone level starts declining and andropause corresponds to the age at which a pathogenic threshold is reached. This review summarizes the etiology, consequences, screening, diagnosis, monitoring of androgen deficiency in aging male (ADAM). The pros and cons of testosterone replacement therapy (TRT) in elderly male have been discussed. Currently oral, transdermal, transbuccal, intramuscular, and subcutaneous implants are available for clinical use. The choice is made by physicians based on therapeutic indication and patient preferences.Key Words: Andropause, Aging male, Testosterone replacement therapy     

Multisite Pacing as a Supplemental Treatment of Congestive Heart Failure: Preliminary Results of the Medtronic Inc. InSync Study

This report describes the initial results of the "InSync" study, a European and Canadian multicenter trial that examines the safety and efficacy of a multisite pacemaker (Medtronic InSync) and of left ventricular pacing leads (Medtronic 2187 and 2188) implanted via a cardiac vein as a supplemental treatment of refractory congestive heart failure. Over a 10-month period, the system was implanted successfully in 68 of the 81 (84%) patients who had been enrolled in the study. The 68 patients were, on average, 66 ± 10 years old, had a mean left ventricular ejection fraction (LVEF) = 21 %± 9%, and 63% were in NYHA functional Class III and 37% were in Class IV. No system implant related complication occurred. During follow-up, 7 of 10 patients who exited the study had died, 4 suddenly. There was a clinical benefit among surviving patients, which was corroborated by a significant improvement in NYHA functional class and in the Minnesota Living with Heart Failure Quality of Life Questionnaire Score (MLS) and by a longer distance covered during a 6-minute walk test. This clinical improvement was associated with a significant narrowing of the paced QRS complex during biventricular pacing, a significant decrease in the interventricular mechanical delay, and a trend towards an increase in the duration of ventricular filling. These encouraging preliminary results confirm the feasibility and reliability of this new multisite pacing system in the management of dilated cardiomyopathy and support the continuation of further evaluations of this complementary treatment of refractory congestive heart failure.     

Understanding the Genomic Structure of Copy‐Number Variation of the Low‐Affinity Fcγ Receptor Region Allows Confirmation of the Association of FCGR3B Deletion with Rheumatoid Arthritis

Fcγ receptors are a family of cell–surface receptors that are expressed by a host of different innate and adaptive immune cells, and mediate inflammatory responses by binding the Fc portion of immunoglobulin G. In humans, five low‐affinity receptors are encoded by the genes FCGR2A , FCGR2B , FCGR2C , FCGR3A , and FCGR3B , which are located in an 82.5‐kb segmental tandem duplication on chromosome 1q23.3, which shows extensive copy‐number variation (CNV). Deletions of FCGR3B have been suggested to increase the risk of inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis (RA). In this study, we identify the deletion breakpoints of FCGR3B deletion alleles in the UK population and endogamous native American population, and show that some but not all alleles are likely to be identical‐by‐descent. We also localize a duplication breakpoint, confirming that the mechanism of CNV generation is nonallelic homologous recombination, and identify several alleles with gene conversion events using fosmid sequencing data. We use information on the structure of the deletion alleles to distinguish FCGR3B deletions from FCGR3A deletions in whole‐genome array comparative genomic hybridization (aCGH) data. Reanalysis of published aCGH data using this approach supports association of FCGR3B deletion with increased risk of RA in a large cohort of 1,982 cases and 3,271 controls (odds ratio 1.61, P = 2.9×10^?3).     

Pathology of Human Pheochromocytoma and Paraganglioma Xenografts in NSG Mice

A major impediment to the development of effective treatments for metastatic or unresectable pheochromocytomas and paragangliomas has been the absence of valid models for pre-clinical testing. Attempts to establish cell lines or xenografts from human pheochromocytomas and paragangliomas have previously been unsuccessful. NOD-scid gamma (NSG) mice are a recently developed strain lacking functional B-cells, T-cells, and NK cells. We report here that xenografts of primary human paragangliomas will take in NSG mice while maintaining their architectural and immunophenotypic characteristics as expressed in the patients. In contrast to grafts of cell lines and of most common types of primary tumors, the growth rate of grafted paragangliomas is very slow, accurately representing the growth rate of most pheochromocytomas and paragangliomas even in metastases in humans. Although the model is therefore technically challenging, primary patient-derived xenografts of paragangliomas in NSG mice provide a potentially valuable new tool that could prove especially valuable for testing treatments aimed at eradicating the small tumor deposits that are often numerous in patients with metastatic paraganglioma.     

Paragangliomas: Update on differential diagnostic considerations,composite tumors,and recent genetic developments

Recent developments in molecular genetics have expanded the spectrum of disorders associated with pheochromocytomas (PCCs) and extra-adrenal paragangliomas (PGLs) and have increased the roles of pathologists in helping to guide patient care. At least 30% of these tumors are now known to be hereditary, and germline mutations of at least 10 genes are known to cause the tumors to develop. Genotype–phenotype correlations have been identified, including differences in tumor distribution, catecholamine production, and risk of metastasis, and types of tumors not previously associated with PCC/PGL are now considered in the spectrum of hereditary disease. Important new findings are that mutations of succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 (collectively “SDHx”) are responsible for a large percentage of hereditary PCC/PGL and that SDHB mutations are strongly correlated with extra-adrenal tumor location, metastasis, and poor prognosis. Further, gastrointestinal stromal tumors and renal tumors are now associated with SDHx mutations. A PCC or PGL caused by any of the hereditary susceptibility genes can present as a solitary, apparently sporadic, tumor, and substantial numbers of patients presenting with apparently sporadic tumors harbor occult germline mutations of susceptibility genes. Current roles of pathologists are differential diagnosis of primary tumors and metastases, identification of clues to occult hereditary disease, and triaging of patients for optimal genetic testing by immunohistochemical staining of tumor tissue for the loss of SDHB and SDHA protein. Diagnostic pitfalls are posed by morphological variants of PCC/PGL, unusual anatomic sites of occurrence, and coexisting neuroendocrine tumors of other types in some hereditary syndromes. These pitfalls can be avoided by judicious use of appropriate immunohistochemical stains. Aside from loss of staining for SDHB, criteria for predicting risk of metastasis are still controversial, and “malignancy” is diagnosed only after metastases have occurred. All PCCs/PGLs are considered to pose some risk of metastasis, and long-term follow-up is advised.     

The CT/CBCT-based team approach to care. Part I: Identiying the implant patient and prosthetic options

Through a CBCT-based team meeting, the surgical team, restorative dentist, and laboratory team member can better coordinate dental implant treatment on many levels. Once the desired restorative result has been established through conventional means, the information can then be transferred via a radiographic template during the scan acquisition. The type of implant, angulation, width and diameter of the implant, and need for grafting, can be determined with great accuracy. This effective exchange of information can take place during an online meeting at a convenient time for all parties. The treatment planning that is possible within the framework of this digital workflow defines the essence of a team approach to implant reconstruction. The protocol as described in part I of this 3-part series allows for improved diagnosis, treatment planning, and successful clinical outcomes. Part 2 of this series will focus on the surgical aspects of the team approach, in collaboration with the restorative clinician and diagnostic imaging center.     

A STUDY OF HYPERINSULINAEMIA AND DYSLIPIDAEMIA IN HYPERTENSIVE PATIENTS OF ARMED FORCES

All patients attending the outpatient department were screened for hypertension. An attempt was made to correlate presence of hyperinsulinaemia (HI), dyslipidaemia and anthropometric characteristics in these hypertensives. Effect of angiotensin converting enzyme inhibitor (ACEI) and beta blockers on serum insulin was also studied. 85 patients with blood pressure (BP) ≥ 160/90 mm Hg and 94 controls with a BP of < 130/85 mm Hg were studied. All underwent clinical examination, anthropometric measurements (body mass index (BMI), waist hip ratio (WHR), skin fold thickness (SFT) and laboratory investigation (serum insulin, glucose, lipid profile) and post oral glucose load (POGL) for insulin and glucose. Serum insulin was estimated by I¹²⁵ radio immuno assay. Patients were randomly divided into group A (Tab enalapril) and group B (Tab atenolol). In 51 patients who completed the study, fasting and POGL insulin and fasting lipid profile were estimated two months after treatment. Mean age of cases was 38.91 years. 50% of patients had stage II hypertension. BMI was increased in 36 cases (42.35%) as compared to 9 in (9.57%) controls. Increased WHR was found in 40 cases as compared to 26 in controls. The SFT was more in cases compared to controls. 47 (55.29%) of 85 cases had abnormal lipid profile as compared to 25 (26.60%) in 94 controls. The fasting and POGL insulin levels (13.85 and 60.05 micro u/ml respectively) in cases were significantly higher than in controls (6.87 and 16.16 micro u/ml respectively). The mean POGL insulin values were much higher in obese compared to non-obese hypertensives. The decrease in mean fasting and POGL insulin values in patients taking ACEI and beta blockers were similar. Abnormal lipid profile was significantly more in cases than controls. Increased total cholesterol (TC), Low density lipoprotein cholesterol (LDLC) and total cholesterol (TC)/high density lipoprotein (HDL) ratio were the most frequent abnormality. The mean insulin (both fasting and POGL) levels were higher in obese hypertensives and those with abnormal lipid profile. Both drugs had equal efficacy in reducing the insulin values.KEY WORDS: Angiotensin converting enzyme inhibitor, Beta-blockers, Body mass index, Hyperinsulinaemia     

Increased uptake of [¹²³I]meta-iodobenzylguanidine, [¹⁸F]fluorodopamine, and [³H]norepinephrine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors

[131I]meta-iodobenzylguanidine ([131I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [123I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [(3)H]norepinephrine, [123I]MIBG, and [(18)F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [(3)H]norepinephrine, [123I]MIBG, and [(18)F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [(18)F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1 ± 3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9 ± 0.6%; P<0.001). Biodistribution analysis after inhibitors treatment confirmed the PET results. The uptake of [(123)I]MIBG was significantly increased in liver metastases 9.5 ± 1.1% compared to 3.19 ± 0.4% in untreated control liver metastases (P<0.05). We found that HDAC inhibitors caused an increase in the amount of norepinephrine transporter expressed in tumors. HDAC inhibitors may enhance the therapeutic efficacy of [(131)I]MIBG treatment in patients with advanced malignant pheochromocytoma and paraganglioma.