What is new in cryptorchidism and hypospadias--a critical review on the testicular dysgenesis hypothesis

It has been hypothesized that poor semen quality, testis cancer, undescended testis, and hypospadias are symptoms of one underlying entity—the testicular dysgenesis syndrome—leading to increasing male fertility impairment. Though testicular cancer has increased in many Western countries during the past 40 years, hypospadias rates have not changed with certainty over the same period. Also, recent studies demonstrate that sperm output may have declined in certain areas of Europe but is probably not declining across the globe as indicated by American studies. However, at the same time, there is increasing recognition of male infertility related to obesity and smoking. There is no certain evidence that the rates of undescended testes have been increasing with time during the last 50 years. In more than 95% of the cases, hypospadias is not associated with cryptorchidism, suggesting major differences in pathogenesis. Placental abnormality may occasionally cause both cryptorchidism and hypospadias, as it is also the case in many other congenital malformations. The findings of early orchidopexy lowering the risk of both infertility and testicular cancer suggest that the abnormal location exposes the cryptorchid testis to infertility and malignant transformation, rather than there being a primary abnormality. Statistically, 5% of testicular cancers only are caused by cryptorchidism. These data point to the complexity of pathogenic and epidemiologic features of each component and the difficulties in ascribing them to a single unifying process, such as testicular dysgenesis syndrome, particularly when so little is known of the actual mechanisms of disease.     

Everolimus for renal cell carcinoma: predictive factors for response and future directions

Mammalian target of rapamycin (mTOR) inhibitors have emerged as a major addition to the therapeutic armamentarium for renal cell carcinoma. Temsirolimus extended survival when employed as frontline therapy for poor-risk advanced renal cell carcinoma. Everolimus has demonstrated improved progression-free survival for all risk groups of RCC in the salvage setting following other anti-angiogenic agents. Preliminary data indicates that baseline activation of the mTOR signaling pathway and increased FDG-PET uptake as well as early pharmacodynamic modulations of the mTOR pathway and down-modulation of FDG-PET uptake may predict for the activity of mTOR inhibitors. Ongoing trials are attempting to validate these data with everolimus therapy for metastatic RCC and may enable the goal of personalized therapy.     

Localization of calcitonin gene-related peptide within the genitofemoral nerve in immature rats.

BACKGROUND/PURPOSE: Calcitonin gene-related peptide (CGRP) has been proposed to influence migration and testicular descent by release from the genitofemoral nerve. The site of CGRP within the nerve has been controversial, with conflicting views on whether CGRP is synthesised and released from the motor nerves. METHODS: The genitofemoral nerve (GFN) was retrogradely labelled by fluorescent dye (DAPI) in 25 Sprague-Dawley rats (days 5, 16, and 31, n = 8 in each group; day 35, n = 1). Spinal cords and dorsal root ganglia (DRG) were removed two to three days later and sectioned for immunofluorescence. Substance P and CGRP-containing cells were labelled with fluorescein-linked antibodies. Specimens were examined by double fluorescence to identify cells with both markers. RESULTS: The motor nucleus of the GFN contained 119 cells on day 7 and 284 cells by days 19 through 34. A prominent band of CGRP-containing fibers, arising from the dorsal horn, synapsed with the GFN motor nucleus itself. CGRP-labelled GFN cells were found in the DRG by double labelling. CONCLUSIONS: CGRP from the GFN may affect gubernacular migration by release from the sensory nerves, rather than motor nerves as previously thought. The GFN motor nucleus receives CGRP-containing innervation from the dorsal horn, which may form part of the cremasteric reflex.     

Assessment of complex peptide degradation pathways via structured multicompartmental modeling approaches: the metabolism of dynorphin A1-13 and related fragments in human plasma.

Peptide metabolic pathways in blood or other tissues are often complex because multiple enzyme systems are involved in the degradation of parent drug and its metabolites. Michaelis-Menten-type studies with isolated enzymes have been frequently employed for evaluating the metabolism of peptides. Alternatively, studies with selective enzyme inhibitors or the evaluation of the area under the drug- or metabolite-time profiles have been employed. We tested in this study the usefulness of a multicompartmental pharmacokinetic approach for the assessment of the apparent first-order metabolism of dynorphin A1-13 up to the fourth metabolite generation in human plasma. This multicompartmental kinetic analysis proved instrumental in clarifying ambiguous degradation pathways not easily detectable by the other methods of assessment (enzyme inhibition studies and noncompartmental analysis) because of the lack of specific enzyme inhibitors or specificity problems of the analytical technique employed. The proposed multicompartmental fitting approach was also highly suitable to verify the overall metabolic pathways suggested by the other methods up to the fourth metabolite by testing whether the rate constants obtained by these methods are suitable to describe the overall degradation profile after Dyn A1-13 degradation. Local sensitivity analysis for the degradation of DYNA 1-13 revealed that the model was, however, not able to adequately identify on its own all of the parameters involved in the degradation of dynorphin A1-13. Thus, the method proved beneficial in evaluating and testing the correctness of the overall degradation pathways suggested by other methods.     

Deep venous thrombosis of the leg: US findings

In a prospective study, 121 consecutive patients with a clinical diagnosis of deep venous thrombosis of the leg were examined with real-time ultrasonography. The findings were correlated with the results of venography. The common femoral vein and the popliteal vein were evaluated for intraluminal echoes and compressibility, and the common femoral vein was also evaluated for an increase in diameter in response to the Valsalva maneuver. The superficial femoral vein and the calf veins were not evaluated. The results indicate that compressibility of the common femoral and popliteal veins is the best indication of deep venous thrombosis, with a sensitivity of 96% and a specificity of 97%. The accuracy of detection was not improved by including data from thrombus visualization or the response of the common femoral vein to the Valsalva maneuver.     

The sensory contribution of a single vibrissa's cortical barrel

The sensory contribution of the cortex containing the cortical barrel of the C1 vibrissa was studied in rats using the ablation-behavior method. Three independent experiments were performed, each requiring stimulus transduction by the C1 vibrissa but varying in their perceptual demands. The first required detection of sinusoidal oscillations of the vibrissa generated by an oscillating airstream directed vertically onto the vibrissa tip. The second required detection of a change in rate of the oscillation. The third required the blinded rat to jump a gap in an elevated runway after palpating the far side with its vibrissa. Psychophysical determinations of the single vibrissa system's thresholds before and after ablation of the cortex containing its barrel show that normal sensitivity either for detecting an oscillation or for detecting a change in oscillation frequency are not dependent on either the contralateral or the ipsilateral cortical barrelfield. In contrast to the lack of effect of barrelfield ablation on the spatial and temporal acuity of the vibrissa, the third experiment shows that a rat's ability to collect situation-relevant information with the vibrissa is lost after ablation of the cortex containing its contralateral barrel but not after ablation of the cortex containing its homologous ipsilateral barrel. The results of repeated retesting of an individual rat's ability to make a jump-no jump decision on the basis of vibrissa-transduced information at each stage of a series of successive single-vibrissa removals and unilateral barrelfield ablations show that the loss of the cortex containing the vibrissa's contralateral barrel is tantamount to loss of the vibrissa itself.     

Platelets of the Wistar Furth rat have reduced levels of alpha-granule proteins. An animal model resembling gray platelet syndrome.

Rats of the Wistar Furth (WF) strain have hereditary macrothrombocytopenia (large mean platelet volume [MPV] with increased platelet size heterogeneity and reduced platelet count). Ultrastructural studies suggest that this anomaly results from erratic subdivision of megakaryocyte cytoplasm into platelets. In this study, we have examined protein profiles of platelets of WF rats for biochemical abnormalities associated with this anomaly. Marked decreases in protein bands with an Mr of 185, 57, 53, 16, 13, and 8 kd were observed in one-dimensional reduced SDS-PAGE gels in WF platelets compared with platelets of Wistar, Long Evans, and Sprague-Dawley rats. These proteins were released into the supernatant when washed platelets were treated with thrombin suggesting that they were alpha-granule proteins. These abnormalities were not present in offspring of crosses between Wistar Furth and Wistar rats; however, they were present in platelets of offspring with large MPV derived from backcrosses of (WF X Wistar) F1 males to WF females, but not in backcross offspring with normal platelet size. Immunoblotting confirmed decreased levels of thrombospondin, fibrinogen, and platelet factor 4 in WF platelets. Electron microscopic examination revealed that platelet alpha granules were usually smaller in Wistar Furth than in Wistar rats. In addition, immunogold electron microscopy demonstrated that the surface connected canalicular system of the large Wistar Furth platelets, contained dense material composed of alpha-granule proteins, not present in Wistar platelets. From these results, we conclude that the Wistar Furth rat platelet phenotype of large mean platelet volume and decreased levels of alpha-granule proteins represents an animal model resembling gray platelet syndrome. The autosomal recessive pattern of inheritance of the large MPV phenotype and platelet alpha-granule protein deficiencies suggests that a component common to both formation of platelet alpha granules, and subdivision of megakaryocyte cytoplasm into platelets, is quantitatively or qualitatively abnormal in Wistar Furth rat megakaryocytes and platelets.