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Abstract: This study assessed patient perceptions of using a smaller needle (1-inch, 25- gauge) to administer weekly intramuscular (IM) interferon beta-1a (IFN[beta]-1a [Avonex]) injections. Patients received 1 IM IFN[beta]-1a injection [...]

Testosterone, classically used to treat hypogonadism, is rapidly gaining popularity as an elixir for youth and virility. The perception that testosterone can counter the symptoms of aging, which seems to [...]

Study objectives: To determine the outcome of patients with pulmonary catheter-induced pulmonary artery pseudoansurysms (PSAs) treated with embolization. Design: Retrospective outcomes review. Setting: Large urban tertiary-care hospital. Patients: All patients [...]

Background: The observation that dehydroepiandrosterone (DHEA) concentrations decrease markedly with age has led to the hypothesis that declining DHEA concentrations may contribute to age-related changes in cognition. In the United States, DHEA is widely available as an over-the-counter supplement that individuals are using in an effort to ameliorate age-related cognitive and physical changes. Objective: To investigate the relationship between age-associated decreases in endogenous DHEA sulfate (DHEA-S) concentrations and declines in neuropsychological performance in a prospective, longitudinal study. Methods: The subjects were 883 men from a community-dwelling volunteer sample in the Baltimore Longitudinal Study of Aging. The men were aged 22 to 911 years at the initial visit, and they were followed up for as long as 31 years (mean, 11.55 years), with biennial reassessments of multiple cognitive domains and contemporaneous measurement of serum DHEA-S concentrations. Outcome measures were the results of cognitive tests of verbal and visual memory, 2 tests of mental status, phonemic and semantic word fluency tests, and measures of visuomotor scanning and attention. Serum DHEA-S concentrations were determined by standard radioimmunoassay. Results: Neither the rates of decline in mean DHEA-S concentrations nor the mean DHEA-S concentrations within individuals were related to cognitive status or cognitive decline. A comparison between the highest and lowest DHEA-S quartiles revealed no cognitive differences, despite the fact that these groups differed in endogenous DHEA-S concentration by more than a factor of 4 for a mean duration of 12 years. Conclusions Our longitudinal results augment those of previous prospective studies by suggesting that the decline in endogenous DHEA-S concentration is independent of cognitive status and cognitive decline in healthy aging men. Arch Intern Med. 2000; 160:2193-2198

Three years of testosterone supplementation in older men attenuated the age-related decline in aerobic capacity. This effect may be explained, at least in part, by changes in hemoglobin levels.

Serum testosterone levels and insulin sensitivity both decrease with age. Severe testosterone deficiency is associated with the development of insulin resistance. However, the effects of long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels remain unknown.

Endogenous testosterone levels have been negatively associated with QTc interval in small case series; the effects of testosterone therapy on electrocardiographic parameters have not been evaluated in randomized trials.

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Findings of studies of testosterone's effects on muscle strength and physical function in older men have been inconsistent; its effects on muscle power and fatigability have not been studied.

The effects of testosterone on cognitive function in older men are incompletely understood. We aimed to establish the effects of long-term testosterone administration on multiple domains of cognitive function in older men with low or low-to-normal testosterone concentrations.

As many as 20–55% of patients with a history of traumatic brain injury (TBI) experience chronic endocrine dysfunction, leading to impaired quality of life, impaired rehabilitation efforts and lowered life expectancy. Endocrine dysfunction after TBI is thought to result from acceleration–deceleration forces to the brain within the skull, creating enduring hypothalamic and pituitary neuropathology, and subsequent hypothalamic–pituitary endocrine (HPE) dysfunction. These experiments were designed to test the hypothesis that a single diffuse TBI results in chronic dysfunction of corticosterone (CORT), a glucocorticoid released in response to stress and testosterone. We used a rodent model of diffuse TBI induced by midline fluid percussion injury (mFPI). At 2months postinjury compared with uninjured control animals, circulating levels of CORT were evaluated at rest, under restraint stress and in response to dexamethasone, a synthetic glucocorticoid commonly used to test HPE axis regulation. Testosterone was evaluated at rest. Further, we assessed changes in injury-induced neuron morphology (Golgi stain), neuropathology (silver stain) and activated astrocytes (GFAP) in the paraventricular nucleus (PVN) of the hypothalamus. Resting plasma CORT levels were decreased at 2months postinjury and there was a blunted CORT increase in response to restraint induced stress. No changes in testosterone were measured. These changes in CORT were observed concomitantly with altered complexity of neuron processes in the PVN over time, devoid of neuropathology or astrocytosis. Results provide evidence that a single moderate diffuse TBI leads to changes in CORT function, which can contribute to the persistence of symptoms related to endocrine dysfunction. Future experiments aim to evaluate additional HP-related hormones and endocrine circuit pathology following diffuse TBI.

A series of chlorinated bisindole pyrroles, lynamicins A−E ( 1− 5), was discovered from a novel marine actinomycete, NPS12745, which was isolated from a marine sediment collected off the coast of San Diego, California. Close to full length 16S rRNA sequence analysis indicated that NPS12745 is a novel strain of a recently described marine actinomycete with the proposed genus name Marinispora.The antimicrobial spectrum of these compounds was evaluated against a panel of 11 pathogens, which demonstrated that these substances possess broad-spectrum activity against both Gram-positive and Gram-negative organisms. Significantly, compounds 1− 5were active against drug-resistant pathogens such as methicillin-resistant Staphylococcus aureusand vancomycin-resistant Enterococcus faecium.

Salinosporamide A (NPI-0052; 3), a highly potent inhibitor of the 20S proteasome, is currently in phase I clinical trials for the treatment of cancer. During the course of purifying multigram quantities of 3from Salinispora tropicafermentation extracts, several new salinosporamides were isolated and characterized, most of which represent modifications to the chloroethyl substituent at C-2. Specifically, 3was isolated along with the known compound salinosporamide B (4), the previously undescribed methyl congener salinosporamide D (7), and C-2 epimers of 3and 7(salinosporamides F (9) and G (10), respectively). Salinosporamide I (13), in which the methyl group at the ring junction is replaced with an ethyl group, and the C-5 deshydroxyl analogue salinosporamide J (14), were also identified. Replacement of synthetic sea salt with sodium bromide in the fermentation media produced bromosalinosporamide (12), 4, and its C-2 epimer (11, salinosporamide H). In addition to these eight new salinosporamides, several thioester derivatives were generated semisynthetically. IC50values for cytotoxicity against human multiple myeloma cell line RPMI 8226 and inhibition of the chymotrypsin-like (CT-L) activity of purified rabbit 20S proteasomes were determined for all compounds. The results indicate that thioesters may directly inhibit the proteasome, albeit with reduced potency compared to their -lactone counterparts.

Observational studies suggest that postmenopausal hormone therapy (HT) prevents coronary heart disease, whereas randomized clinical trials have not confirmed a cardioprotective effect. Although observational studies may have overestimated the coronary benefit conferred by postmenopausal hormone use, there are other plausible explanations for the apparent discrepancy between previous results and the less favorable findings from clinical trials such as the large Women's Health Initiative. There is now a critical mass of data to support the hypothesis that age or time since menopause may importantly influence the benefit-risk ratio associated with HT, especially with respect to cardiovascular outcomes, and that the method of administration, dose, and formulation of exogenous hormones may also be relevant. Although the weight of the evidence indicates that older women and those with subclinical or overt coronary heart disease should not take HT, estrogen remains the most effective treatment currently available for vasomotor symptoms, and its effects on the development of coronary disease in newly postmenopausal women remain unclear. Moreover, effects of HT on quality of life and cognitive function in recently postmenopausal women merit further study. These unresolved clinical issues provide the rationale for the design of the Kronos Early Estrogen Prevention Study, a 5-year randomized trial that will evaluate the effectiveness of low-dose oral estrogen and transdermal estradiol in preventing progression of atherosclerosis in recently postmenopausal women.

The Women’s Health Initiative (WHI) hormone replacement therapy (HRT) estrogen plus progestin (E+P) and estrogen-only arms are part of a large NIH-sponsored randomized controlled trial (RCT). Both arms were terminated prematurely after 5 and 8 yr, respectively. The E+P arm showed non-statistically significant increased incidences of cardiovascular events and breast cancer, whereas the E-only arm did not. Both arms showed an increased rate of thromboembolic events and stroke. Both arms showed protection against fractures and with protection against colon cancer only in the E+P arm. These results have been widely generalized as indicating a negative risk/benefit ratio for HRT in menopausal women.

Our study documents a comprehensive simultaneous analysis of the association between five-audit committee composition and operational characteristics features and earnings management based on a sample of 485 organisational-years of Singapore publicly traded organisations. Findings provide only partition support for the view organisations with a higher proportion of independent audit committee members are more effective at constraining earnings management. Organisations with audit committees that are more diligent and/or lack the presence of independent directors serving simultaneously on a substantial number of boards and committees are more effective at constraining earnings management. Audit committee expertise and the presence of a senior executive director on the committee do not appear to influence the committee's ability to constrain earnings management. Our findings are robust to alternative income-incentives facing corporate management and entices associated with different levels of ownership concentration. Overall, our findings are rich with policy and practical implications.

Recently we reported that the pyridinylimidazole class of p38 mitogen-activated protein (MAP) kinase inhibitors potently inhibited the facilitated transport of nucleosides and nucleoside analogs in K562 cells. These compounds competed with the binding of nitrobenzylthioinosine (NBMPR) to K562 cells, consistent with inhibition of the NBMPR-sensitive equilibrative transporter (ENT1). In this study we examined a large number of additional protein kinase inhibitors for their effects on nucleoside transport. We find that incubation of K562 cells with tyrosine kinase inhibitors (AG825, AG1517, AG1478, STI-571), protein kinase C (PKC) inhibitors (staurosporine, GF 109203X, R0 31-8220, arcyriarubin A), cyclin-dependent kinase inhibitors (roscovitine, olomoucine, indirubin-3'-monoxime), or rapamycin resulted in a dose-dependent reduction of intracellular uptake of [3H]uridine. In contrast, neither the MAP kinase kinase inhibitors (U0126, PD 98059) nor the phosphatidyl inositol-3 kinase inhibitors (wortmannin, LY 294002) affected this process. Furthermore, both transient uptake and prolonged [3H]thymidine incorporation in K562 cells were inhibited by protein kinase inhibitors, inactive analogs of kinase inhibitors (R0 31-6045, SB202474), and NBMPR, independently of effects on cell proliferation as determined by MTT assay. These studies demonstrate that a wide variety of protein kinase inhibitors affect nucleoside uptake through selective inhibition of nucleoside transporters, independently of kinase inhibition.

Decreases in growth hormone (GH) and insulin-like growth factor I occur with age, in addition to oestrogen deficiency in women and a reduction in the levels of testosterone in men. These age-related hormonal changes may contribute to reductions in lean body mass, muscle strength and cardiac endurance, which can be partially reversed in elderly people with GH treatment, and testosterone supplements and oestrogen/progestin hormone replacement therapy in men and women, respectively. These treatments are, however, thought to have potentially serious adverse effects. We conducted a study to evaluate the separate and interactive effects of GH and sex steroids on body composition, muscle strength and cardiac endurance as well as the rate of adverse events in healthy elderly people. The results of the study showed that although there were beneficial effects with GH and sex steroid treatment, a high percentage of adverse effects occurred after 26 weeks of treatment, demonstrating a need for more research on the safety of hormonal therapy in the elderly population.

A77 1726 (LEF) is the active metabolite of leflunomide, a recently approved immunosuppressive agent. We examined the ability of LEF to induce differentiation of a human erythroleukemia (K562) cell line and show that LEF induces a dose- and time-dependent differentiation of these cells as characterized by growth inhibition, hemoglobin production, and erythroid membrane protein glycophorin A expression. This effect was dependent on depletion of the intracellular pyrimidine ribonucleotides (UTP and CTP), and preceded by a specific S-phase arrest of the cell cycle. Supplementation of the cultures with exogenous uridine restored intracellular UTP and CTP to normal levels and prevented the LEF-induced cell cycle block and differentiation of K562 cells. Interestingly, addition of cytidine alone blocked the LEF-induced differentiation of K562 cells but only restored the CTP pool. By contrast, neither deoxycytidine nor thymidine prevented the effects of LEF on these cells. Similarly, pyrimidine starvation of a cell line lacking the de novo pyrimidine pathway (G9c) resulted in an S-phase arrest that was reversed by the addition of cytidine. Thus these studies demonstrate an important role for CTP in regulating cell cycle progression and show that LEF is an effective inducer of tumor cell differentiation through depletion of this ribonucleotide.

No discrete event marks a transition to male reproductive senescence; however, a number of investigations have suggested that male fertility and reproductive hormone secretion decrease with age, giving rise to the term male menopause. Nearly all studies of seminiferous tubular function and morphology have found evidence of an age-related deterioration including anatomical lesions, reduced semen quality, elevated serum levels of inhibin, and diminished fertility. The question of altered androgen secretion remains controversial with evidence both for and against age-related reductions in testosterone (T), free T, and/or DHT in multiple investigations. Much of this controversy probably stems from noncompar-able populations, especially with regard to confounding variables such as stress, illness, and medication use. Published findings to date agree that in healthy aging men there is a small but significant increase in basal levels of LH and a diminished T response to exogenous gonadotropin, suggesting an intrinsic loss of Leydig cell reserve. Moreover, there is evidence of a gradual loss of function of the hypodialamic/pituitary gonadotropic axis as well. Despite these changes, healthy aging men appear to maintain normal circulating total and free T and DHT levels, despite modest increases in sex hormone binding globulin (SHBG) and an small downward trend in serum androgens. Whether there are metabolic consequences such as altered body composition, muscle strengdi, and lipid profiles in the portion of the aging male population with larger androgen decrements requires further investigation.

We have developed a novel semipermeable chamber for intraabdominal culture of primate gametes and embryos. Application of the egg-embryo chamber offers a unique opportunity to study fertilization and preimplantation embryogenesis. Intrinsically normal monkey embryos displayed timely cleavage and symmetric form when cultured in this intraabdominal chamber for up to 72 hours. The birth of the first normal live monkey infant derived from the egg-embryo chamber is reported.

The healing rate of full-thickness skin lesions is slower in senescent female rats (22-23 months) than in their young adult (5-6 months) counterparts. Fifty percent wound closure times were 9.46 ± 0.31 and 6.45 ± 0.40 days, respectively (P< 0.001). Ovariectomy significantly slows the healing process in the mature group but not in the senescent animals. Treatment of ovariectomized rats with low-dose estradiol (0.3 μg/kg body wt) restores the healing rate to nearly normal in mature rats and accelerates the healing rate relative to sham-operated controls in senescent rats. Thus, decreased healing rates in senescent female rats may be due in part to reduced estrogenic potentiation of healing.

Abstract: Vascular injuries during laparoscopic cholecystectomy can occur in an analogous fashion to biliary injuries, with potential laceration, transection, and occlusion of blood vessels. A patient presented with symptomatic hemobilia 1 month following laparoscopic cholecystectomy and was found to have a right hepatic artery pseudoaneurysm which communicated with the common bile duct. This was successfully embolized with several embolic agents, resulting in rapid resolution of all signs and symptoms. The patient has been free of symptoms during a follow-up period of 1 year. A brief discussion of hepatic artery pseudoaneurysms is presented.

A 54-year-old woman with relapsing-remitting multiple sclerosis (MS) developed visual loss in her left eye due to a macular hemorrhage 11 months after starting fingolimod. Visual acuity was 2080 in the left eye, with a dense retinal hemorrhage involving the fovea with adjacent hard exudate and macular thickening confirmed by spectral domain optical coherence tomography. Three months after stopping fingolimod, vision in the left eye improved to 2030 with resolution of the macular hemorrhage and exudates. Fingolimod has been associated with macular edema, but prior to this report, the authors are unaware of it causing a macular hemorrhage in a MS patient. The authors speculate that the macular hemorrhage may be due to a disruption of cellular adhesions between vascular endothelial cells that maintain the inner blood–retinal barrier.

Introduction. Anorectal malformations (ARM) are complex disorders that often require staged reconstructions. We present a case and imaging findings of a child who developed issues following colostomy closure due to segmental colonic ischemia. Case Presentation. A 3-year-old female with Currarino syndrome presented with abdominal distention, blood-flecked stools, and prolonged cecostomy flush time. For her anorectal malformation, a colostomy was initially placed. A new colostomy was created at posterior sagittal anorectoplasty (PSARP) to allow the distal rectum to reach the anus without tension. Differentials for her presenting symptoms included a mislocation of the anus, stenosis at the anoplasty site, stricture within the colon, or sacral mass from Currarino syndrome, causing obstructive symptoms. Workup at our hospital included an anorectal exam under anesthesia (EUA), which showed a well-located anus with without stenosis at the anoplasty site, and an antegrade contrast study revealed a featureless descending colon with a 3-4 mm stricture in the distal transverse colon at the site of the previous colostomy, without an obstructing presacral mass. To alleviate this obstruction, the child underwent removal of the chronically ischemic descending colon and a redo-PSARP, where the distal transverse colon was brought down to the anus. She is now able to successfully perform antegrade flushes. Conclusion. Patients who have had prior surgeries for ARM repair are at a higher risk of complications, including strictures or ischemic complications at areas of previous surgery or colostomy placement. A thorough preoperative workup, including contrast studies, can alert the surgeon to these potential pitfalls.

Condensation products of β-cyclodextrin with propylene oxide or epichlorohydrin, which are amorphous and thus very soluble in water, were used to form complexes with testosterone, progesterone, and estradiol. Sublingual/buccal administration of tablets of these complexes led to effective absorption and entry of the hormones into the systemic circulation, followed by gradual elimination; rapid first-pass loss was avoided. β-Cyclodextrin itself, its 2,6-dimethyl derivative, and a nonionic detergent did not enable effective buccal absorption. Absorption from the Gl tract of hormones complexed with hydrophilic cyclodextrins was also less effective. Effective absorption of drugs from the oral cavity requires (a) that the drug and solubilizer form a complex of the inclusion type which dissolves completely and rapidly and (b) that the solubilizer neither enters nor damages oral tissue.

Background. Trigger finger is a relatively common clinical entity. The etiology is most often attributable to stenosing tenosynovitis though traumatic cases have been described. When trigger finger is associated with an underlying flexor tendon rupture, previous cases have reported a clear association with overt laceration or previous trauma. Methods. We present the case of a 23-year-old male active duty military service member who presented with a characteristic history and clinical exam consistent with trigger finger. The symptomatic onset was gradual, with no history of inciting trauma. Results. Given symptomatic persistent triggering following failure of conservative management to include cortisone injections, the patient was taken for open A1 pulley release. Intraoperatively, the triggering was found to be attributable to a partial attritional rupture of the small finger flexor digitorum profundus tendon. Tendon debridement, tubularization, and A1 and partial A2 pulley releases were performed with subsequent resolution of triggering. Conclusion. We present the rare case of subclinical atraumatic attritional rupture of the FDP tendon to the small finger as a cause of clinically apparent trigger finger. This is an important consideration as the hand surgeon must be prepared to address more atypical pathologies.

AIMS: Patients with upper gastrointestinal haemorrhage (UGIH) are usually admitted to hospital regardless of the severity of the bleed. The aim of this study was to identify patients who could be safely managed without hospitalisation and immediate inpatient endoscopy. METHODS: Based on a literature review, a protocol was devised using clinical and laboratory data regarded as being of prognostic value. A retrospective observational study of consecutive patients who attended the emergency department (ED) with UGIH was conducted during one calendar month. RESULTS: Fifty four patients were identified of whom 44 (81%) were admitted. Twelve suffered an adverse event. One of the 10 patients (10%) initially discharged from the ED was later admitted. Strict implementation of the protocol would have resulted in safe discharge of a further 15 patients, (34% of those admitted), and a saving of an estimated 37 bed days per month. CONCLUSIONS: Patients at low risk from UGIH may be identified in the ED. If validated, this protocol may improve patient management and resource utilisation.

A recently-devised scheme for partitioning crystal space into smooth molecular volumes is used to visualise intermolecular interactions in the crystal structures of naphthalene and terephthalic acid.

The article argues about human optimism stating if God can be satisfied with his creations as depicted in the bible, humans should maintain optimism too.

Connective tissue is one of the body's most pervasive tissues and is responsible for producing and maintaining form in nearly every organ in the body. It functions in a mechanical role, producing a matrix that serves to support and protect most of the major organ systems. Because connective tissues have such an important function, most of the major connective tissue diseases are either life threatening or crippling with enormous impact on healthcare cost. Diseases of connective tissues are manifested by either increased breakdown of connective tissues, as in osteoarthritis and osteoporosis, or overproduction of connective tissues, as in scleroderma and hepatic fibrosis.