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     

Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients

The morbidity and lethality of AL amyloidosis is caused by the deposition of lg light chains as fibrillar amyloid protein in vital organs, disrupting their function, and not by the generally low burden of clonal plasma cells that produce the paraproteins. Survival of patients with AL amyloidosis is no more than 1 to 2 years from the time of diagnosis with current management approaches. Clearly, more effective therapies are needed for this rapidly lethal disease. Five patients were treated with dose-intensive melphalan and blood stem cell support and followed for a period of 1 year. Patients were diagnosed with AL amyloidosis by tissue biopsy and categorized by performance status and organ involvement. Their plasma cell dyscrasias were evaluated with immunofixation electrophoresis of serum and urine specimens, quantitative serum lgs, and immunohistochemical staining of bone marrow biopsy specimens. After treatment with dose-intensive intravenous melphalan followed by infusion of autologous growth-factor- mobilized blood stem cells, clinical evaluations and plasma cell studies were repeated at 3 and 12 months. Three men and 2 women aged 38 to 53 years were treated. Median performance status (SWOG) was 2 (1 to 3), and clinical presentations included nephrotic syndrome (n = 1), symptomatic cardiomyopathy (n = 1), gastrointestinal involvement with polyneuropathy (n = 2), and hepatomegaly (n = 1). With a median follow- up of 13 months (12 to 17 months), all five patients are well and have shown stable or improved performance status and clinical remission of organ-related dysfunction, including a 50% reduction in daily proteinuria with no change in creatinine, reversal of symptoms of cardiomyopathy and reductions of posterior wall and septal thickening, reversal of polyneuropathy and gastric atony, and resolution of hepatomegaly by computed tomographic scan. In 3 of the 5 patients (60%) at 12 months after treatment, plasma cell dyscrasias could not be detected. Dose-intensive chemotherapy with intravenous melphalan and growth-factor-mobilized blood stem cell support is feasible therapy for patients with AL amyloidosis, even when there is clinical evidence of cardiac involvement. At least some patients with AL amyloidosis achieve complete remission of their plasma cell dyscrasia, improvement in performance status, and clinical remission of organ-specific disease after this form of treatment.     

Pseudo-Bernard-Soulier syndrome: thrombocytopenia caused by autoantibody to platelet glycoprotein Ib

The Bernard-Soulier syndrome is an inherited bleeding disorder that is due to a deficiency in platelet glycoprotein Ib. Bernard-Soulier platelets fail to agglutinate in response to ristocetin despite normal levels of factor VIII:von Willebrand factor. We report a patient who developed severe refractory thrombocytopenia postsurgically while receiving procainamide therapy. Thrombocytopenia was immune mediated since the patient's platelets bore high levels of antiplatelet antibody. Radioimmunoprecipitation studies demonstrated that the autoantibodies had specificity for platelet glycoproteins Ib and V as well as platelet HLA. The patient's plasma as well as purified immunoglobulin G completely inhibited the ristocetin-induced aggregation of normal platelets but did not inhibit adenosine diphosphate-induced aggregation. The laboratory studies revealed that this patient suffered from antibody-mediated thrombocytopenia with unusual characteristics that we have called pseudo-Bernard-Soulier syndrome.     

Transgenic rescue implicates beta2-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD) mice

Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from T-cell-mediated autoimmune destruction of insulin-producing pancreatic beta cells. Linkage studies have shown that type 1 diabetes in NOD mice is a polygenic disease involving more than 15 chromosomal susceptibility regions. Despite extensive investigation, the identification of individual susceptibility genes either within or outside the major histocompatibility complex region has proven problematic because of the limitations of linkage analysis. In this paper, we provide evidence implicating a single diabetes susceptibility gene, which lies outside the major histocompatibility complex region. Using allelic reconstitution by transgenic rescue, we show that NOD mice expressing the beta(2) microglobulin (beta(2)M)(a) allele develop diabetes, whereas NOD mice expressing a murine beta(2)M(b) or human allele are protected. The murine beta(2)M(a) allele differs from the beta(2)M(b) allele only at a single amino acid. Mechanistic studies indicate that the absence of the NOD beta(2)M(a) isoform on nonhematopoietic cells inhibits the development or activation of diabetogenic T cells.     

MHC antigen induction by interferon gamma on cultured mouse pancreatic beta cells and macrophages. Genetic analysis of strain differences and discovery of an "occult" class I-like antigen in NOD/Lt mice

This study provides a basis for understanding the wide variations reported in the literature in IFN-gamma inducibility of class II MHC antigens on murine beta cells. Inducibility is not an intrinsic property of all mouse beta cells, but instead depends upon strain- (and tissue-) specific response modifying factors. This was demonstrated by comparison of constitutive and IFN-gamma-induced class I and class II MHC gene products on cultured islet cell monolayers. Islet cultures were established from autoimmune diabetes-prone NOD/Lt mice, diabetes-resistant NON/Lt and CBA/J mice, as well as F1 hybrids between these latter two strains and NOD/Lt. Cultures of peritoneal macrophages (M phi) from each strain were established as controls. After 3 wk of culture (with incubation in the presence or absence of IFN-gamma during the last 6 d), constitutive expression as well as IFN-gamma induction of class I MHC antigen expression was demonstrated on NOD/Lt and NON/Lt islet cells by antibody plus complement-mediated cytotoxicity. Although CBA/J islets and M phi did not maintain constitutive class I or class II antigen expression in culture in the absence of IFN-gamma, class I H-2Kk antigen was IFN-gamma inducible. Whereas IFN-gamma-induced class II I-Ak antigen on CBA/J M phi, it failed to induce this antigen on CBA/J islets. In contrast, I-A antigens were IFN-gamma inducible on NOD/Lt and NON/Lt islets and M phi. In (CBA x NOD)F1 hybrids, loss of IFN-gamma inducibility of the I-ANOD product established that suppression was mediated by a trans-acting factor from the CBA/J genome. In the course of these studies, IFN-gamma inducibility of a crossreactive occult class I-like antigen on both NOD/Lt islet cell and M phi cultures was unexpectedly detected when mAb 28-13-3 (public specificity 39, reactive with H-2Kb,f) was used as a negative control. Although not detectable by cytofluorographic analysis of freshly isolated NOD/Lt splenic leukocytes, occult antigen could be induced on NOD/Lt peritoneal macrophages (M phi) cultured for 3 d in IFN-gamma. Time course of induction showed the occult antigen to be distinct from NOD/Lt class I and II gene products. In both islet cell and M phi cultures established from (CBA x NOD)F1 hybrids, trans-suppressive factor(s) from the CBA/J genome not only suppressed IFN-gamma-induced expression of I-ANOD, but additionally suppressed occult antigen induction. Backcross of F1 to both parental strains indicated that the occult locus was on Chr 17, tightly linked to MHC.(ABSTRACT TRUNCATED AT 400 WORDS)     

Steady‐state amprenavir and tenofovir pharmacokinetics after coadministration of unboosted or ritonavir‐boosted fosamprenavir with tenofovir disoproxil fumarate in healthy volunteers

Objective

An open‐label, three‐period pharmacokinetic study was conducted to investigate the drug interaction potential between fosamprenavir (FPV) and tenofovir disoproxil fumarate (TDF).

Methods

Thirty‐six healthy subjects received TDF 300 mg once daily (qd) for 7 days (period 1), and then were randomized to 14 days of either FPV 1400 mg twice daily (bid) or FPV/ritonavir (RTV) 700/100 mg bid alone or with TDF (period 2). Subjects continued their randomized dose of FPV for 14 more days, adding or removing TDF based upon its receipt in period 2 (period 3). Twenty‐four‐hour pharmacokinetic sampling was carried out on day 7 of period 1 and on day 14 of periods 2 and 3. Steady‐state plasma amprenavir (APV) and tenofovir (TFV) pharmacokinetics were assessed by noncompartmental analysis and parameter values observed with each regimen were compared using geometric mean ratios with 90% confidence intervals.

Results

After TDF coadministration, APV geometric mean minimum concentration (C_min), maximum concentration (C_max), and area under the plasma concentration–time curve (AUC) increased by 31, 3 and 7% above values observed with unboosted FPV alone; they also increased by 31, 4 and 16% above values observed with FPV/RTV alone. TFV C_min, C_max and AUC decreased by 12, 25 and 15% after FPV coadministration and by 9, 18 and 7% after FPV/RTV coadministration. No significant changes in RTV pharmacokinetics were observed. No differences were noted in adverse events among dosing periods.

Conclusions

In this evaluation of the interaction between FPV and TDF, increases in APV exposures and modest decreases in TFV exposures were observed. These were unlikely to be clinically significant.