Mentel, Ferdinand Mercado, Denny J. Were you to substitute Alexander Pavlovich a été l'unique buteur du côté du Bélarus. Rooney, Sam Roop, Andrew W. The animal locates a mine and then deposits a weighted buoy line near the mine in order to mark it. Born Hepburn 12 September died 3 December
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Historical background materials made possible by Archibald Andrews Marks. Questions and Answers 2. Autodesk Official Training Guides, the recommended study materials to help users prepare for An Introduction to Java Computer Programming. Why did you write this book? I enjoy programming and I There have been many questions asked about the Memorandum of Settlement. This letter is to answer One approach to reduce sperm output is by exploiting the essential requirement for retinoic acid in spermatogenesis Experimental genetic or pharmacological inhibition of vitamin A action inhibits the generation of mature sperm and male fertility , ; however, the ubiquitous roles of vitamin A in cellular replication and differentiation requires thorough safety evaluation for off-target effects in clinical trials.
Another series of orally active indazole carboxylic acid analogs, adjudin, gamendazole and indenopyridine derivatives , have been developed from the lead compound lonidamine but aiming to eliminating its non-specific muscle and liver toxicity while retaining its mechanism of action in causing reversible male infertility.
The indazole carboxylic acid analogs cause reversible subfertility by disrupting highly specialized intercellular junctions between elongating spermatids and Sertoli cells leading to precocious detachment of immature, elongating spermatids which are shed prematurely from the germinal epithelium.
Clinical evaluation of such drugs remains at an early stage. The seclusion of functionally immature post-meiotic, haploid sperm during their transit through seminiferous tubules and epididymis offers targets for chemical methods to regulate male fertility as sperm are stored and mature functionally. Post-testicular targets offer the advantages of fast onset and offset of action compared with hormonal methods; however, specific target identification, selective drug targeting to the epididymis or testis and human dose optimisation remain challenging problems.
A model, rapid-onset oral spermicide was first provided by the chlorosugars that showed rapid, irreversible effect on rodent epididymal sperm but proved too toxic for clinical development. A recent promising drug lead was the recognition that an alkylated iminosugar drugs that inhibit glucosyltransferase, used therapeutically to reduce lysosomal glycosphingolipid accumulation in storage disorder type 1 Gaucher's disease , miglustat, was a potent and reversible oral inhibitor of male mouse fertility but free from apparent systemic toxicity , Miglustat treatment produced structural malformation of sperm acrosome, head and mid-piece with consequential impaired motility although sperm retain the ability to fertilize oocytes in-vitro and produce normal offspring.
However, miglustat effects were species- and mouse strain-dependent and were not effective in rabbits or men Numerous proteins identified as specifically or uniquely expressed in the epididymis provide additional opportunities for development of novel non-hormonal male contraceptive targets Post-testicular inhibition of purinergic and adrenergic receptors in the vas deferens to inhibit sperm movement through the ejaculatory ducts are feasible , ; however, interference with ejaculation is unlikely to be an acceptable form of male contraception.
The most rapidly growing area of opportunity arises from serendipitous discoveries of genes found to be necessary for normal fertility, often from gene knock-out mouse models displaying unexpected male sterility or subfertility This rapidly expanding list includes distinctive steps in spermatogenesis involving either biological processes unique to spermatogenesis, notably meiosis two-stage reductive division of diploid germinal cells into haploid gametes and spermiogenesis metamorphosis of haploid round spermatids into spermatozoa or inhibiting functions essential to sperm fertilizing ability such as flagellar motility and sperm motion including hyperactivation , excurrent ductular transport, acrosome reaction, chemoattraction to and fertilization of oocytes , and acrosomal function The most frequent mechanisms involve inhibition of ion channels in sperm , or vas deferens smooth muscle , leading to inhibition of fertilization.
One leading candidate is CatSper, the principal calcium channel activated by progesterone and essential for the sperm hyperactivation required for fertilization Experimental vaccines against catsper epitopes do inhibit mutine fertility , The genes highlighted in a previous review are in black, with new genes identified since then and others not shown previously in blue. Communication between each cellular compartment within the testis seminiferous tubules, interstitial cells and blood vessels, as well as between individual cell types germ cells, Sertoli cells, peritubular myoid cells, Leydig cells and macrophages play essential parts in mitosis, meiosis and differentiated function.
It is noteworthy that the genes fall into specific categories of function, such as those involved in signal transduction, homologous recombination or energy production. Gene targeting in the mouse models has provided new insights into potential etiologies of male infertility. Hormonal methods are the closest to meeting the requirement for a reliable, reversible, safe and acceptable male contraceptive.
Although reliability is judged by the efficacy in preventing pregnancy in fertile female partners, as a hormonal male contraceptive aims to prevent pregnancy by reversible inhibition of sperm output, the suppression of spermatogenesis constitutes a useful surrogate marker for development and evaluation of prototype male contraceptive regimens. This makes defining the degree of suppression of sperm output required a key strategic issue in developing a hormonal male contraceptive Two landmark WHO studies, the first ever male contraceptive efficacy studies, involving men from 16 centres in 10 countries established the proof of principle that hormonally-induced azoospermia provides highly reliable, reversible contraception 10, Hence to achieve highly effective contraception, azoospermia is analogous to anovulation as a sufficient, but not necessary, requirement.
Nevertheless, reliable contraception by modern standards 19 requires uniform azoospermia as the desirable target for male contraceptive regimens No regimen yet achieves this consistently in all men, although in some Asian countries e.
China 11 , Indonesia , an approximation to uniform azoospermia can be achieved by a variety of regimens. A study involving Chinese men in 6 centres has shown that monthly injections of testosterone undecanoate provides highly effective and reversible contraception The prototype regimen was well tolerated apart from injection site discomfort due to large oil injection volume 4 mL and reversible androgenic effects acne, weight gain, hemoglobin, lipids.
Nevertheless, despite these promising findings, non-Chinese men require combination hormonal regimens involving a 2nd gonadotropin suppressing agent, notably progestins, together with testosterone to ensure adequate spermatogenic suppression. Ultimately, the efficacy of male contraception must be established by enumerating pregnancies prevented, and not counting sperm. The present paucity of male contraceptive efficacy studies, for which placebo controls are effectively impossible , makes systematic evaluations comparing practical clinical regimens a task for the future This comprehensive review of the recovery of healthy eugonadal men, aged years, who underwent Covariables such as age, ethnicity and hormonal or sperm output kinetics had significant but minor influence on the rate, but not the extent, of recovery.
Acceptability of a hormonal male contraceptive is high across a wide range of countries and cultures in potential male as well as female users 9. A majority of men in a US study were satisfied with and would recommend a transdermal gel-based hormonal contraceptive and a majority of Chinese men were satisfied with even frequent monthly injections Corroborating the acceptability of hormonal male contraception are findings from experimental studies of prototype regimens for up to 12 months usage in which most participants confirm high levels of satisfaction and willingness to try a commercial product , , , Modern safety evaluation for hormonal contraceptive methods requires long-term, large scale studies of marketed products Consequently, in the absence of any marketed male contractive, no long-term safety profile can be discerned.
Nevertheless, 4 decades of clinical trials have consistently identified mainly minor adverse effects in short- or medium term studies of prototype male hormonal contraception regimens 1, 5, This was verified in a unique, placebo-controlled study of a combined androgen-progestin regimen which again proved highly effective at reversible suppression of sperm output although the inclusion of a placebo arm rendered it ethically impossible to evaluate contraceptive efficacy but provided insight into drug-related side effects 8.
The study confirmed the benign medium-term safety profile for this prototype regimen in observing few serious adverse effects, none attributable to the steroid regimen, and, among the non-serious adverse effects reported, expected androgenic effects acne, weight gain, sweating, changes in mood or libido were more frequent than placebo but mild and rarely led to discontinuation 8.
Nevertheless, the long-term safety evaluation of novel contraceptives requires large scale observational studies of extensively used drugs to define low frequency risks but can only occur after the marketing of suitable products.
Hence, prototype hormonal methods have proven reliability and reversibility and reasonable prospects for being well accepted and safe. Although they are the most likely opportunity in the foreseeable future to develop a practical contraceptive method for men, progress depends on pharmaceutical industry development. However, leadership in male contraceptive development has come almost exclusively from the academics working with public sector organisations 5 , notably WHO , CONRAD and the Population Council By contrast, commitment from pharmaceutical companies, including those that flourished in the post-war decades through developing female hormonal contraception, continued to languish over recent decades 16, and is effectively ceased Testosterone provides both gonadotropin suppression and androgen replacement making it an obvious first choice as a single agent for a reversible hormonal male contraceptive.
Although androgen-induced, reversible suppression of human spermatogenesis has long been known , systematic studies of androgens for male contraception began in the 's , Feasibility and dose-finding studies , mostly using testosterone enanthate TE in an oil vehicle as a prototype, showed that weekly im injections of mg TE induce azoospermia in most Caucasian men but less frequent or lower doses fail to sustain suppression The largest experience with an androgen alone regimen arises from the two WHO studies in which over men from 16 centres in 10 countries received weekly injections of mg TE.
The high efficacy among Chinese men has also been replicated using monthly TU injections 12, Effective gonadotropin suppression is a prerequisite for effective testosterone-induced spermatogenic suppression in human 14, and non-human primates , However, the reasons for within and between population differences in susceptibility to hormonally-induced azoospermia remain largely unexplained While it is postulated that the very high ambient intratesticular testosterone typically times circulating testosterone concentrations must be fully suppressed by complete inhibition of circulating LH, which maintains it , limited invasive studies measuring intratesticular testosterone and DHT suggest that the degree of depletion may not predict reliably complete suppression of sperm output Other more widely applicable, non-invasive markers of endogenous Leydig cell function such as circulating epitestosterone or hydroxyprogesterone or non-steroidal testicular products such as INSL3 may be informative as to the relative roles of gonadotropin suppression and intratesticular androgen depletion.
Following cessation of treatment, sperm reappear within 3 months to reach sperm densities of 10 and 20 million per mL at an average of Apart from intolerance of weekly injections, there were few discontinuations due to acne, weight gain, polycythemia or behavioral effects and these were reversible as were changes in hemoglobin, testis size and plasma urea.
There was no evidence of liver, prostate or cardiovascular disorders 10, 11, The pharmacokinetics of testosterone products are crucial for suppressing sperm output. Oral androgens have major first-pass hepatic effects producing prominent route-dependent effects on hepatic protein secretion eg SHBG, HDL cholesterol and inconsistent bioavailability. Short-acting testosterone products requiring daily or more frequent administration oral, transdermal patches or gels which may be acceptable for androgen replacement therapy are not appropriate for hormonal contraception.
Weekly TE injections required for maximal suppression of spermatogenesis are far from ideal and cause supraphysiological blood testosterone levels risking both excessive androgenic side effects and preventing maximal depletion of intratesticular testosterone for optimal efficacy , Other currently available oil-based testosterone esters cypionate, cyclohexane-carboxylate, propionate are no improvement over the enanthate ester , and longer-acting depot preparations are needed.
Subdermal testosterone pellets sustain physiological testosterone levels for months and the newer injectable preparations testosterone undecanoate 13 , testosterone-loaded biodegradable microspheres and testosterone buciclate provide months duration of action.
Depot androgens suppress spermatogenesis faster, at lower doses and with fewer metabolic side effects than TE injections but azoospermia is still not achieved uniformly although when combined with a depot progestin, this goal is achievable Oral synthetic a alkylated androgens such as methyltestosterone , fluoxymesterone , methandienone and danazol , suppress spermatogenesis but azoospermia is rarely achieved and the inherent hepatotoxicity of the a alkyl substitutent , renders them unsuitable for long-term use.
Athletes self-administering supratherapeutic doses of androgens also exhibit suppression of spermatogenesis , On the other hand, nandrolone hexyloxyphenylpropionate alone was unable to maintain spermatogenic suppression induced by a GnRH antagonist in a prototype hybrid regime where induction and maintenance treatment differ whereas testosterone appears more promising More potent, synthetic androgens lacking a alkyl groups , remain to be evaluated.
Antiandrogens have been used to selectively inhibit epididymal and testicular effects of testosterone without impeding systemic androgenic effects Cyproterone acetate, a steroidal antiandrogen with progestational activity, suppresses gonadotropin secretion without achieving azoospermia but leads to androgen deficiency when used alone In contrast, pure non-steroidal antiandrogens lacking androgenic or gestagenic effects such as flutamide, nilutamide and casodex fail to suppress spermatogenesis when used alone , Two studies evaluating the hypothesis that incomplete suppression of spermatogenesis is due to persistence of testicular DHT have reported no additional suppression from administration of finasteride, a type II 5a reductase inhibitor , ; however as testes express predominantly the type I isoforms , further studies are required to conclusively test this hypothesis using an inhibitor of type I 5-a reductase Adverse effects due to testosterone administration in prototype hormonal contraceptive regimens include asymptomatic polycythemia, weight muscle gain and acne as well as changes in mood or sexual behaviour.
These are usually minor in severity, reversible upon cessation of treatment and of minimal clinical significance 8. The safety of androgen administration concerns mainly potential effects on cardiovascular and prostatic disease As the explanation for the higher male susceptibility to cardiovascular disease is not well understood, the risks of exogenous androgens are not clear , In clinical trials, lipid changes are minimal with depot non-oral hormonal regimens 14, , , The real cardiovascular risks or benefits of hormonal male contraception will require long-term surveillance of cardiovascular outcomes The long-term effects of exogenous androgens on the prostate also require monitoring since prostatic diseases are both age and androgen-dependent.
Exposure to adult testosterone levels is required for prostate development and disease The precise relationship of androgens to prostatic disease and in particular any influence of exogenous androgens remains poorly understood. Ambient blood testosterone or DHT levels do not predict development of prostatic cancer over future decades in prospective studies of adults A genetic polymorphism, the CAG polyglutamine triplet repeat in exon 1 of the androgen receptor, is an important determinant of prostate sensitivity to circulating testosterone with short repeat lengths leading to increased androgen sensitivity , however the relationship of the CAG triplet repeat length polymorphism to late-life prostate diseases remains unclear Among androgen deficient men, prostate size and PSA concentrations are reduced and returned towards normal by testosterone replacement without exceeding age-matched eugonadal controls , In healthy middle-aged men without known prostate disease, very high doses of the potent natural androgens DHT for 2 years did not increase prostate size or age-related growth rate compared with placebo indicating that effects of even high dose exogenous androgen treatment has much less effect than age on the human prostate Similarly, self-administration of massive androgen over-dosage does not increase total prostate volume or PSA in anabolic steroid abusers although central prostate zone volumes increases In-situ prostate cancer is common in all populations of older men whereas rates of invasive prostate cancer differ many-fold between populations despite similar blood testosterone concentrations.
This suggests that early and prolonged exposure to androgens may initiate in-situ prostate cancer but later androgen-independent environmental factors promote the outbreak of invasive prostate cancer.
Therefore it is prudent to maintain physiological androgen levels with exogenous testosterone, which then might be no more hazardous than exposure to endogenous testosterone. Prolonged surveillance comparable with that for cardiovascular and breast disease in users of female hormonal contraception would be equally essential to monitor both cardiovascular and prostatic disease risk in men receiving exogenous androgens for hormonal contraception. Extensive experience with testosterone in doses equivalent to replacement therapy in normal men indicates minimal effects on mood or behavior 10, 11, , A careful placebo-controlled, cross-over study showed that a mg TU injection in healthy young men produces minor mood changes without any detectable increase in self or partner-reported aggressive, non-aggressive or sexual behaviors By contrast, extreme androgen doses used experimentally in healthy men can produce idiosyncratic hypomanic reactions in a minority Aberrant behaviour in observational studies of androgen-abusing athletes or prisoners are difficult to interpret particularly to distinguished genuine androgen effects from the influence of self-selection for underlying psychological morbidity Combination steroid regimens use non-androgenic steroids estrogens, progestins to suppress gonadotropins, in conjunction with testosterone for androgen replacement, have shown the most promising efficacy with enhanced rate and extent of spermatogenic suppression compared with androgen alone regimens , , Synergistic combinations reduce the effective dose of each steroid and minimising testosterone dosage could enhance spermatogenic suppression if high blood testosterone levels counteract the necessary maximal depletion of intratesticular testosterone , as well as reducing androgenic side-effects.
Progesterone is a key precursor and steroidogenic intermediate for all bioactive natural steroids and the progesterone receptors A and B are structurally and evolutionarily the closest members of the nuclear receptor superfamily to the androgen receptor. Yet, although progesterone has crucial gestational and lactational roles in female reproductive physiology, it has no well established role in male reproductive physiology apart from a possible role in sperm function , , possibly via non-genomic rather than a classically genomic mechanism Nevertheless functional nuclear progesterone receptors are expressed in male brain, smooth muscle and reproductive, but not most non-reproductive, tissues Synthetic progestins, steroidal structural agonistic analogs of progesterone, are potent inhibitors of pituitary gonadotropin secretion used widely for female contraception and hormonal treatment of disorders such as endometriosis, uterine myoma and mastalgia.
Used alone, progestins suppress spermatogenesis but cause androgen deficiency including impotence , so androgen replacement is necessary. Non-human primate studies indicate that this is mediated via a central hypothalamic-pituitary site of action rather than direct effects on the testis Extensive feasibility studies concluded that progestin-androgen combination regimens had promise as hormonal male contraceptives if more potent and durable agents were developed , Nearly uniform azoospermia is produced in men treated with depot MPA and either of two injectable androgens in Indonesian men , or testosterone depot implants in Caucasian men Smaller studies with other oral progestins such as levo-norgestrel , , and norethisterone , combined with testosterone demonstrate similar efficacy to oral MPA whereas cyproterone acetate with its additional anti-androgenic activity has higher efficacy in conjunction with TE , but not oral testosterone undecanoate Highly effective suppression of spermatogenesis is reported with depot progestins in the form of non-biodegradable implants of norgestrel or etonorgestrel , or depot injectable medroxyprogesterone acetate 14, , , or norethisterone enanthate , coupled with testosterone.
The pharmacokinetics of the testosterone preparation is critical to efficacy of spermatogenic suppression with long-acting depots being most effective while transdermal delivery is less effective than injectable testosterone Progestin side-effects are few if sexual function and well being are maintained by adequate doses of testosterone replacement.
The metabolic effects depend on specific regimen with oral administration and higher testosterone doses exhibiting more prominent hepatic effects such as lowering SHBG and HDL cholesterol. After treatment ceases with depletion or withdrawal of hormonal depots, spermatogenesis recovers completely but gradually consistent with the time-course of the spermatogenic cycle , Estradiol augments testosterone-induced suppression of primate spermatogenesis and fertility but estrogenic side-effects gynecomastia and modest efficacy at tolerable doses make estradiol-based combinations impractical for male contraception The efficacy and tolerability of newer estrogen analogs in combination with testosterone remain to be evaluated.
The pivotal role of GnRH in the hormonal control of testicular function makes it an attractive target for biochemical regulation of male fertility. Many superactive GnRH agonists are used to induce reversible medical castration for androgen-dependent prostate cancer by causing a sustained, paradoxical inhibition of gonadotropin and testosterone secretion and spermatogenesis due to pituitary GnRH receptor downregulation.
By contrast, pure GnRH antagonists create and sustain immediate competitive blockade of GnRH receptors , and, in combination with testosterone, are highly effective at suppressing spermatogenesis. Early hydrophobic GnRH antagonists were difficult to formulate and irritating, causing injection site mast cell histamine release. Newer more potent but less irritating GnRH antagonists produce rapid, reversible and complete inhibition of spermatogenesis in monkeys and men , when combined with testosterone.
The striking superiority of GnRH antagonists over agonists may be due to more effective and immediate inhibition of gonadotropin secretion and thereby more effective depletion of intratesticular testosterone. Poulomi will fight it out with Veronika Pavlovich of Bulgaria on September 17 and French woman Anne Boileau the following day for the right to figure in the main draw.
She will need to draw from all her vast experience to make a fight of it. Twenty-two-year old Chanu may be not as well known as her senior team-mate, but two experts have predicted here in newspapers and journals that she can end up with a silver or a bronze medal as she is rated the No 2 in the world currently in the 53 kg class.
But she has to fight her way in a field which has at least three others who have produced better results than the little Indian ironwoman. The fortunes of the rowers, participating in the Olympics for the first time, will be clearer after the draw is made later today. For the athletes, who are still coming here in batches, the D-Day is a week away. Paes and his partner Mahesh Bhupathi, who ended as world No 1 pair on the ATP rankings, have been drawn to meet the crack Australian combination of Mark Woodforde and Todd Woodbridge in the second round.
While the Woodies, seeded No 1, got the first round bye in the team main draw, the Indian tandem of Paes and Bhupathi will face a first round hurdle in modest Romanian pair of Andrei Pavel and Gabriel Trifu in the top half. The all-conquering Indians, before their acrimoniuos split early this year, have beaten the Aussie pair twice on the circuit.
But the Olympics being a swansong for the Woodies and the competition being held at home, the Indians have a formidable task on hand. Should the Indians get past the retiring combination when the event starts here on Tuesday, their path to the medals round looks quite clear. If Paes crosses the first hurdle, sixth-seeded American Michael Chang is his likely opponent in the second round. And further ahead Briton seventh-seeded Tim Henman will be waiting to face the Indian.
The duo have since agreed to mend their differences but they are struggling to find their previous form. The year-old prodigy, powered by size 17 feet, has exerted such domination in the metres freestyle this year that he could win the event by the largest margin in nearly a century.
Nobody has won the freestyle by more than 3. Thorpe posted a world record three minutes Thorpe himself wisely refuses to regard himself as certain to win the m.
But his rivals are already scattering. World champion Michael Klim pulled out of the m to concentrate on better gold medal chances elsewhere. Sludnov set a world record of 1: Australia has the metres freestyle with Ian Thorpe and I can nullify that swim. Australians, roaring Thorpe on in the 17,capacity indoor pool centre and millions more watching on television cannot be expected to believe a word of it.
Will Sydney pass the test? Optimism rules and the early signs suggest that they will get it right and the world will go home with a hangover enriched by fond memory. Nothing fascinates the media as much as a debacle. As a resident of Australia I have an Olympics wish list. People who will be watching it all on television will dearly hope that the excellent Qantas advertisement showing Australian children in different parts of the world and much of it in India, the Taj Mahal and the Rajasthan desert is not played too often.
Americans however were not paying a lot of attention to the Sydney Olympics preoccupying the rest of the world but that changed as the games hit their TV guides this week.
But in case the SOCOG and the Australian Tourism Commission are breaking out champagne over this success of their public relations endeavours, they should hold on to the fizz. Only now, with the Olympics underway, has some kind of consciousness of the other looming extravaganza descended on bits of New York. This week well into the pre-Olympic home stretch, the New York Times finally published its guide to the games, complete with feature pieces on Ian Thorpe and Cathy Freeman.
Perhaps it was a glitch in the transmission of the piece from Sydney or maybe The Times just figured that Australians are a weird mob. Ato Boldon, the sprinter from Trinidad and Tobago who is most likely to give Maurice Greene a run for his money, already feels Freeman is part of his extended family. US sports fans are apparently more concerned about what they will not be seeing, or at least when they will not be seeing it. You see when the cold war ended, Americans found that winning had lost some of its lustre.
Beating the Soviet Union was a pleasure.