We aimed to evaluate the presenting features and treatment outcome of prostate cancer in men aged <50 years, in a region where prostate specific antigen (PSA) screening is not readily available and ...most men present with symptoms.
We analysed the data of 1 571 men with prostatic adenocarcinoma treated between January 1997 and December 2008 at out institution, a tertiary level public secotr hospital serving a largely indigent population. Statistical analysis was performed using Student's, the Mann-Whitney and Fisher's exact tests where appropriate (p<0.05 accepted as statistically significant).
Of 1 571 men, 47 (3%) were aged < 50 years. The group aged <50 years compared with that aged >50 years, had a siginificantly greater proportion with poorly differentiated adenocarcinoma (53%), locally advanced (stage T3-4) tumours (56%), haematogenous metastases (75%), significantly higher serum PSA at diagnosis (mean 621, median 74 ng/ml) and shorter survival.
Men aged <50 years presenting with symptoms owing to prostate cancer had significantly higher risk disease, higher mean PSA, and poorer prognosis than men aged >50 years. To diagnose prostate cancer at a potentially curable stage in men aged <50 years, it is necessary to initiate asleine PSA testing at age 40 and 45 years, and to select high-risk men for PSA surveillance in order to diagnose potentially curable cancer in those with a life expectancy >20-25 years.
Previous research suggests that endocrine disrupters (EDCs) like nonylphenol cause apoptosis (both via the intrinsic and extrinsic pathway) and that ROS generation and Ca (2+) play a fundamental role ...in the process. We have investigated morphological changes induced by 17beta-estradiol, nonylphenol, 17alpha-ethynylestradiol and diethylstilbestrol on the IN OVO neural chick embryo model by using transmission and scanning electron microscopy (TEM and SEM). We found that estrogenic substances such as nonylphenol, diethylstilbestrol (DES) and 17alpha-ethynylestradiol, as well as 17beta-estradiol cause ultrastructural changes to developing neurons, resulting in damage to the plasma, mitochondrial as well as nuclear membranes. Furthermore, both apoptotic blebbing and necrotic (or oncotic) budding was seen in TEM and SEM micrographs. SEM shows that nonylphenol-exposed neurons have irregular cell surfaces with pseudopodia, cell shrinkage and breakages in the plasma membrane--typical of apoptosis. TEM indicated that plasma membranes and double nuclear membranes have structural changes, with apoptotic bodies (blebbing) and disrupted mitochondrial membranes. In 17alpha-ethynylestradiol-exposed neurons, disruption of the plasma membrane with cell swelling and vacuolization was present. No apoptotic bodies or budding were noted here. 17beta-Estradiol induced openings in the plasma membrane, while DES-exposed neurons did not show any morphological changes. Therefore we conclude that EDC damage is morphologically visible and the damage is recognized as apoptosis and oncosis. Estrogenic substances may hence modify hormonal actions thereby leaving the developing nervous system more susceptible to damaging events.
The absorption enhancing effects of chitosan and its derivatives have been intensively studied in recent years. It has been shown that these compounds are potent absorption enhancers. Chitosan is ...only soluble in acidic environments and is therefore incapable of enhancing absorption in the small intestine, the main absorption area in the gastrointestinal tract. Special emphasis has been placed on the absorption enhancing properties of
N-trimethyl chitosan chloride (TMC), a partially quaternised derivative of chitosan, due to its solubility in neutral and basic environments. TMC is prepared by the reductive methylation of chitosan. The degree of quaternisation can be altered by increasing the number of reaction steps or by increasing the reaction time. Although the molecular weight of the polymer increases with addition of the methyl groups, a net decrease in the molecular weight is observed due to a decrease in the chain length of the polymer. TMC, like chitosan, possesses mucoadhesive properties. In vitro studies performed on Caco-2 cell monolayers showed a pronounced reduction in the transepithelial electrical resistance (TEER). TMC is also able to increase the permeation of hydrophilic compounds such as
14C-mannitol and
14C polyethylene glycol 4000 (
14C PEG 4000, MW4000) across the cell monolayers. It was also shown that the degree of quaternisation of the polymer plays an important role on its absorption enhancing properties, especially in neutral environments where chitosan is ineffective as an absorption enhancer. The reduction in TEER is an indication of the opening of the tight junctions located between epithelial cells. Opening of the tight junctions will result in enhancement of absorption via the paracellular route. Confocal laser scanning microscopy confirmed transport of large hydrophilic compounds via the paracellular route as well as the mechanism of action of the polymer in which redistribution of the cytoskeletal F-actin is provoked, which leads to the opening of the tight junctions. Various in vivo studies in different animal models confirmed the ability of TMC to increase the absorption of the peptide drugs buserelin and octreotide after intraduodenal or -jejunal administration. However, TMC has always been administered as a solution in these studies. The impracticality of administering a solution, as well as the fact that most peptides are unstable in the presence of water, have led to the need for a solid oral dosage form with which TMC can be administered together with peptide drugs. Recent studies have focused on the development and in vivo evaluation of solid oral dosage forms.
To evaluate temporal changes in male urethral stricture etiology and socio-demographic features by comparing a contemporary with a previously studied cohort.
A total of 125 men with proven urethral ...strictures were interviewed April 2007 through March 2008 using a structured questionnaire on demographic, socio-economic and clinical aspects. The findings were compared with those reported in 120 urethral stricture patients seen at the same institution during 1991. Statistical analysis was performed using analysis of variance (ANOVA) and Fisher's exact tests (p<0.05=statistically significant). The protocol was approved by the local ethics committee.
Compared to the 1991 cohort, the current cohort had a significantly greater proportion with >6 years of schooling (77.5% vs 45.8%), mean number of sex partners (7.3 vs 4.6) and illegal drug use (20.8% vs 10%). Stricture etiology showed a decrease in urethritis (25.6% vs 45%) and external trauma (16.8% vs 28.3%) and an increase in internal (iatrogenic) trauma (36.8% vs 10%). The groups with urethritis and external trauma were significantly younger (mean age 46.1 and 36.3 years) than those with iatrogenic trauma or idiopathic etiology (55.5 and 53.8 years, respectively). Urethritis etiology was associated with a greater number of sex partners, lower education level, previous imprisonment, and illegal drug use.
Over the past 15 years there was an increase in education levels, illegal drug usage and number of sex partners in men with urethral strictures. There was a decrease in urethritis and external trauma, and an increase in iatrogenic trauma as stricture etiology.
Studies addressing the economic impacts of invasive alien species are biased towards ex-post assessments of the costs and benefits of control options, but ex-ante assessments are also required to ...deal with potentially damaging invaders. The polyphagous shot hole borer Euwallacea fornicatus (Coleoptera: Curculionidae) is a recent and potentially damaging introduction to South Africa. We assessed the potential impact of this beetle by working across economic and biological disciplines and developing a simulation model that included dynamic mutualistic relations between the beetle and its symbiotic fungus. We modeled the potential growth in beetle populations and their effect on the net present cost of damage to natural forests, urban trees, commercial forestry, and the avocado industry over 10 yr. We modeled high, baseline, and low scenarios using discount rates of 8, 6, and 4%, and a plausible range of costs and mortality rates. Models predicted steady growth in the beetle and fungus populations, leading to average declines in tree populations of between 3.5 and 15.5% over 10 yr. The predicted net present cost was 18.45 billion international dollars (Int. $), or about 0.66% of the country's GDP for our baseline scenario ($2.7 billion to $164 billion for low and high scenarios). Most of the costs are for the removal of urban trees that die as a result of the beetle and its fungal symbiont, as has been found in other regions. We conclude that an ex-ante economic assessment system dynamics model can be useful for informing national strategies on invasive alien species management.
We have generated a construct encoding a single-chain H-2D(b) mouse MHC class I molecule in which an influenza virus nucleoprotein (NP) epitope, amino acid sequence ASNENMDAM, is fused to mouse ...beta(2)-microglobulin and the D(b) H chain via flexible linker sequences. This single-chain trimer (SCT) was efficiently expressed at the cell surface independently of TAP and endogenous beta(2)-microglobulin, and it was recognized directly and efficiently by specific T cells in vitro. A recombinant vaccinia virus encoding the D(b) NP SCT primed a CD8(+) T cell response in C57BL/6 mice 4-fold greater than an equivalent virus expressing the NP epitope as a minigene, as shown by tetramer staining, whether or not the minigene was directed into the endoplasmic reticulum by a signal sequence. This response was functional as shown by in vivo lysis assays with peptide-pulsed target cells, and it was greatly expanded following secondary challenge in vivo with influenza virus. The SCT was also significantly more immunostimulatory for CD8(+) cells than the NP minigene in adoptive transfer experiments using F5 TCR transgenic spleen cells, in which the magnitude of the T cell response was much greater. Our results extend previous DNA vaccination studies using SCTs, which demonstrated that such molecules are capable of generating functional CD8(+) T cell responses. We have shown that class I SCTs are more immunogenic than even preprocessed Ag in the form of an epitope minigene, and they therefore should be considered for use when the generation of optimal CD8(+) T cell responses is required.
Genome-wide association studies do not always replicate well across populations, limiting the generalizability of polygenic risk scores (PRS). Despite higher incidence and mortality rates of prostate ...cancer in men of African descent, much of what is known about cancer genetics comes from populations of European descent. To understand how well genetic predictions perform in different populations, we evaluated test characteristics of PRS from three previous studies using data from the UK Biobank and a novel dataset of 1298 prostate cancer cases and 1333 controls from Ghana, Nigeria, Senegal, and South Africa.
Allele frequency differences cause predicted risks of prostate cancer to vary across populations. However, natural selection is not the primary driver of these differences. Comparing continental datasets, we find that polygenic predictions of case vs. control status are more effective for European individuals (AUC 0.608-0.707, OR 2.37-5.71) than for African individuals (AUC 0.502-0.585, OR 0.95-2.01). Furthermore, PRS that leverage information from African Americans yield modest AUC and odds ratio improvements for sub-Saharan African individuals. These improvements were larger for West Africans than for South Africans. Finally, we find that existing PRS are largely unable to predict whether African individuals develop aggressive forms of prostate cancer, as specified by higher tumor stages or Gleason scores.
Genetic predictions of prostate cancer perform poorly if the study sample does not match the ancestry of the original GWAS. PRS built from European GWAS may be inadequate for application in non-European populations and perpetuate existing health disparities.
Fadogia homblei, Pavetta harborii, Pavetta schumanniana, Vangueria pygmaea (=Pachystigma pygmaeum), Vangueria latifolia (=Pachystigma latifolium) and Vangueria thamnus (=Pachystigma thamnus) all ...induce one of the most important cardiotoxicoses of domestic ruminants in southern Africa, causing the sickness gousiekte. All the plants which cause gousiekte have previously been shown to contain bacterial endophytes. However, in this study other plants within the Vanguerieae tribe that have not been reported to cause gousiekte; namely Vangueria infausta, Vangueria macrocalyx and Vangueria madagascariensis, have now been shown to also contain endophytes within the inter-cellular spaces of the leaves. The disease gousiekte is difficult to characterise due to fluctuations in plant toxicity. The majority of reported cases of gousiekte poisoning are at the beginning of the growing season; and thus the plants are thought to be more toxic at this time. By using both transmission and scanning electron microscopy the endophytes within these Vanguerieae plants were compared visually. Using the plant reported most often for gousiekte poisoning, V. pygmaea, a basic seasonal comparison of the presence of endophytes was done. It was found that the bacterial endophyte colonies were most abundant during the spring season.
► Non-toxic Vangueria species including V. madagascariensis, do contain endophytes. ► The bacterial endophyte colonies are most abundant during the spring season. ► Endophytes of gousiekte causing species are morphologically different to those of non-pathogenic species.
Ventricular dyssynchrony is a disturbance of the normal, organized electromechanical coupling of the two ventricles. This condition has many causes, such as left bundle branch block, ventricular ...preexcitation, right ventricular pacing and right ventricular premature ventricular complexes (PVCs). Ventricular dyssynchrony has many adverse haemodynamic effects on the left ventricle and we wanted to know whether these adverse haemodynamic effects might have any structural consequences on the left ventricles of such hearts. Six healthy Dorper wethers were subjected to numerous right ventricular PVCs to induce ventricular dyssynchrony in order to determine whether any structural consequences will occur in the left ventricles of these hearts. Myocarditis in the musculature of the left ventricles of all six these hearts was seen.
New radio (MeerKAT and Parkes) and X-ray (XMM-Newton, Swift, Chandra, and NuSTAR) observations of PSR J1622-4950 indicate that the magnetar, in a quiescent state since at least early 2015, ...reactivated between 2017 March 19 and April 5. The radio flux density, while variable, is approximately 100× larger than during its dormant state. The X-ray flux one month after reactivation was at least 800× larger than during quiescence, and has been decaying exponentially on a 111 19 day timescale. This high-flux state, together with a radio-derived rotational ephemeris, enabled for the first time the detection of X-ray pulsations for this magnetar. At 5%, the 0.3-6 keV pulsed fraction is comparable to the smallest observed for magnetars. The overall pulsar geometry inferred from polarized radio emission appears to be broadly consistent with that determined 6-8 years earlier. However, rotating vector model fits suggest that we are now seeing radio emission from a different location in the magnetosphere than previously. This indicates a novel way in which radio emission from magnetars can differ from that of ordinary pulsars. The torque on the neutron star is varying rapidly and unsteadily, as is common for magnetars following outburst, having changed by a factor of 7 within six months of reactivation.
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