Diagnosis and treatment of hypogonadism in men seeking to preserve fertility - what are the options?

Male hypogonadism is a clinical syndrome that results in low testosterone levels and frequently leads to infertility. The syndrome occurs due to disruption at one or more levels of the hypothalamic-pituitary-gonadal axis. Testosterone replacement therapy (TRT) is the most common treatment utilised for male hypogonadism. However, long-acting forms of TRT leads to infertility and so is inappropriate for patients wishing to conceive. For patients who wish to remain fertile, nasal TRT, clomiphene citrate, exogenous gonadotropins, gonadotropin releasing hormone and aromatase inhibitors have been used as alternative treatment options with different degrees of success. A review of the literature was performed to identify the safety and efficacy of alternative treatment options. Gonadotropin releasing hormone can successfully induce spermatogenesis but is impractical to administer. Likewise, aromatase inhibitors have limited use due to inducing osteopenia. Nasal TRT may be a good treatment option for these patients, but its efficacy has so far only been demonstrated in small sample sizes. However, clomiphene citrate and exogenous gonadotropins are safe, offer good symptom control and can successfully induce fertility in hypogonadism patients.

High-physiological and supra-physiological 1,2-13C2 glucose focal supplementation to the traumatised human brain.

How to optimise glucose metabolism in the traumatised human brain remains unclear, including whether injured brain can metabolise additional glucose when supplied. We studied the effect of microdialysis-delivered 1,2-13C2 glucose at 4 and 8 mmol/L on brain extracellular chemistry using bedside ISCUSflex, and the fate of the 13C label in the 8 mmol/L group using high-resolution NMR of recovered microdialysates, in 20 patients. Compared with unsupplemented perfusion, 4 mmol/L glucose increased extracellular concentrations of pyruvate (17%, p = 0.04) and lactate (19%, p = 0.01), with a small increase in lactate/pyruvate ratio (5%, p = 0.007). Perfusion with 8 mmol/L glucose did not significantly influence extracellular chemistry measured with ISCUSflex, compared to unsupplemented perfusion. These extracellular chemistry changes appeared influenced by the underlying metabolic states of patients' traumatised brains, and the presence of relative neuroglycopaenia. Despite abundant 13C glucose supplementation, NMR revealed only 16.7% 13C enrichment of recovered extracellular lactate; the majority being glycolytic in origin. Furthermore, no 13C enrichment of TCA cycle-derived extracellular glutamine was detected. These findings indicate that a large proportion of extracellular lactate does not originate from local glucose metabolism, and taken together with our earlier studies, suggest that extracellular lactate is an important transitional step in the brain's production of glutamine.

Incorporation of a Phosphino(pyridine) Subcomponent Enables the Formation of Cages with Homobimetallic and Heterobimetallic Vertices.

Biological systems employ multimetallic assemblies to achieve a range of functions. Here we demonstrate the preparation of metal-organic cages that contain either homobimetallic or heterobimetallic vertices. These vertices are constructed using 2-formyl-6-diphenylphosphinopyridine, which forms ligands that readily bridge between a pair of metal centers, thus enforcing the formation of bimetallic coordination motifs. Two pseudo-octahedral homometallic MI12L4 cages (MI = CuI or AgI) were prepared, with a head-to-head configuration of their vertices confirmed by X-ray crystallography and multinuclear NMR for AgI. The phosphino-pyridine subcomponent also enabled the formation of a class of octanuclear CdII4CuI4L4 tetrahedral cages, representing an initial example of self-assembled cages containing well-defined heterobimetallic vertices.

Indications and characteristics of penile traction and vacuum erection devices.

A variety of devices are available for the management of patients with erectile dysfunction, Peyronie's disease, penile dysmorphophobia, for support before and after penile prosthesis insertion, and after radical prostatectomy. Traction devices include, but are not limited to, Penimaster PRO (MSP Concept, Berlin, Germany), Andropenis and Andropeyronie (Andromedical, Madrid, Spain), and the Restorex (PathRight Medical, Plymouth, USA). The other type of devices are vacuum devices such the Osbon ErecAid (Timm Medical, MN, USA). Different devices are optimal for different clinical applications, and robust and contemporary clinical data show a variety of strengths and weaknesses for each device. Research currently favours the use of traction devices for improvement of penile curvature and erectile function in patients with Peyronie's disease compared with vacuum devices; Penimaster Pro and Restorex have been shown to be associated with the best outcomes in this indication. Vacuum devices are favoured for treatment of erectile dysfunction and penile length loss after radical prostatectomy; the Osbon ErecAid is the most well-studied device for this indication. Research into other uses of vacuum and traction devices, such as for penile dysmorphophobia or before and after penile prosthesis, is very limited. Compliance, cost and availability remain substantial challenges, and further high-quality evidence is required to clarify the role of traction devices in urology and sexual medicine.

Bladder leiomyoma masquerading as a ureterocele.

We present a unique case of bladder leiomyoma that was mistakenly diagnosed as a ureterocele. The delay in diagnosis meant ongoing significant voiding lower urinary tract symptoms, which could have been avoided. This was eventually successfully treated by transurethral resection. Leiomyoma is the most common benign bladder mass and should be considered in the differential diagnosis when a smooth mass with normal overlying mucosa is seen on cystoscopy or a homogeneous, low density bladder mass is seen on cross-sectional imaging. Despite the benign nature of the lesion, leiomyoma can convey significant morbidity to the patient.

Phosphorus spectroscopy in acute TBI demonstrates metabolic changes that relate to outcome in the presence of normal structural MRI.

Metabolic dysfunction is a key pathophysiological process in the acute phase of traumatic brain injury (TBI). Although changes in brain glucose metabolism and extracellular lactate/pyruvate ratio are well known, it was hitherto unknown whether these translate to downstream changes in ATP metabolism and intracellular pH. We have performed the first clinical voxel-based in vivo phosphorus magnetic resonance spectroscopy (31P MRS) in 13 acute-phase major TBI patients versus 10 healthy controls (HCs), at 3T, focusing on eight central 2.5 × 2.5 × 2.5 cm3 voxels per subject. PCr/γATP ratio (a measure of energy status) in TBI patients was significantly higher (median = 1.09) than that of HCs (median = 0.93) (p < 0.0001), due to changes in both PCr and ATP. There was no significant difference in PCr/γATP between TBI patients with favourable and unfavourable outcome. Cerebral intracellular pH of TBI patients was significantly higher (median = 7.04) than that of HCs (median = 7.00) (p = 0.04). Alkalosis was limited to patients with unfavourable outcome (median = 7.07) (p < 0.0001). These changes persisted after excluding voxels with > 5% radiologically visible injury. This is the first clinical demonstration of brain alkalosis and elevated PCr/γATP ratio acutely after major TBI. 31P MRS has potential for non-invasively assessing brain injury in the absence of structural injury, predicting outcome and monitoring therapy response.

Adsorption of 4-n-Nonylphenol, Carvacrol, and Ethanol onto Iron Oxide from Nonaqueous Hydrocarbon Solvents.

The adsorption of 4-n-nonylphenol (4NP), carvacrol, and ethanol onto the surface of iron oxide from nonaqueous solutions is presented. It is found that adsorption of 4NP from alkanes is strong and proceeds to monolayer formation, where the molecules are essentially "upright". However, at high relative concentrations, ethanol successfully out-competes 4NP for the iron oxide surface. Estimates of the enthalpy and entropy of binding of 4NP were found to be exothermic and entropically disfavored. Sum frequency generation vibrational spectroscopy data indicate some evidence of binding through a phenolate anion, despite the nonpolar, nonaqueous solvent. Carvacrol is also found to adsorb as a monolayer where the molecules are lying "flat". The adsorption of ethanol onto iron oxide from dodecane was investigated through the use of quantitative NMR, which is a convenient analytical technique for measuring adsorption isotherms. It was concluded that ethanol does not form adsorbed monolayers on the surface. Instead, it partitions onto the surface as a surface-enhanced local phase separation related to its poor solubility in alkane solvents.

The effect of succinate on brain NADH/NAD+ redox state and high energy phosphate metabolism in acute traumatic brain injury.

A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31P MRS at 3T, and tissue NADH/NAD+ redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days). Succinate perfusion was associated with increased extracellular pyruvate (+26%, p < 0.0001) and decreased L/P ratio (-13%, p < 0.0001) in patients overall (baseline-vs-supplementation over time), but no clear-cut change in 31P MRS PCr/ATP existed in our cohort (p > 0.4, supplemented-voxel-vs-contralateral voxel). However, the percentage decrease in L/P ratio for each patient following succinate perfusion correlated significantly with their percentage increase in PCr/ATP ratio (Spearman's rank correlation, r = -0.86, p = 0.024). Our findings support the interpretation that L/P ratio is linked to brain energy state, and that succinate may support brain energy metabolism in select TBI patients suffering from mitochondrial dysfunction.

Inguinal hernia causing extrinsic compression of bilateral ureters leading to chronic obstructive uropathy.

Ureteral inguinal hernias are a well-documented cause of obstructive uropathy with ureteric involvement in the hernia sac. In this unique case, the left-sided inguinal hernia causes extrinsic compression of bilateral ureters outside of the hernia sac leading to chronic obstructive uropathy, which is demonstrated on non-contrast CT and cystogram. This patient was managed with nephrostomy and subsequently antegrade stenting with nephrostomy removal. Prior to nephrostomy removal, nephrostogram demonstrated tapering of the left ureter in the pelvis. The patient's renal function continues to improve and is awaiting repair if his inguinal hernia after which he will have his ureteric stent removed.

A Comparison of Oxidative Lactate Metabolism in Traumatically Injured Brain and Control Brain.

Metabolic abnormalities occur after traumatic brain injury (TBI). Glucose is conventionally regarded as the major energy substrate, although lactate can also be an energy source. We compared 3-13C lactate metabolism in TBI with "normal" control brain and muscle, measuring 13C-glutamine enrichment to assess tricarboxylic acid (TCA) cycle metabolism. Microdialysis catheters in brains of nine patients with severe TBI, five non-TBI brain surgical patients, and five resting muscle (non-TBI) patients were perfused (24 h in brain, 8 h in muscle) with 8 mmol/L sodium 3-13C lactate. Microdialysate analysis employed ISCUS and nuclear magnetic resonance. In TBI, with 3-13C lactate perfusion, microdialysate glucose concentration increased nonsignificantly (mean +11.9%, p = 0.463), with significant increases (p = 0.028) for lactate (+174%), pyruvate (+35.8%), and lactate/pyruvate ratio (+101.8%). Microdialysate 13C-glutamine fractional enrichments (median, interquartile range) were: for C4 5.1 (0-11.1) % in TBI and 5.7 (4.6-6.8) % in control brain, for C3 0 (0-5.0) % in TBI and 0 (0-0) % in control brain, and for C2 2.9 (0-5.7) % in TBI and 1.8 (0-3.4) % in control brain. 13C-enrichments were not statistically different between TBI and control brain, showing both metabolize 3-13C lactate via TCA cycle, in contrast to muscle. Several patients with TBI exhibited 13C-glutamine enrichment above the non-TBI control range, suggesting lactate oxidative metabolism as a TBI "emergency option."

Online Quantification of Criegee Intermediates of α-Pinene Ozonolysis by Stabilization with Spin Traps and Proton-Transfer Reaction Mass Spectrometry Detection.

Biogenic alkenes, which are among the most abundant volatile organic compounds in the atmosphere, are readily oxidized by ozone. Characterizing the reactivity and kinetics of the first-generation products of these reactions, carbonyl oxides (often named Criegee intermediates), is essential in defining the oxidation pathways of organic compounds in the atmosphere but is highly challenging due to the short lifetime of these zwitterions. Here, we report the development of a novel online method to quantify atmospherically relevant Criegee intermediates (CIs) in the gas phase by stabilization with spin traps and analysis with proton-transfer reaction mass spectrometry. Ozonolysis of α-pinene has been chosen as a proof-of-principle model system. To determine unambiguously the structure of the spin trap adducts with α-pinene CIs, the reaction was tested in solution, and reaction products were characterized with high-resolution mass spectrometry, electron paramagnetic resonance, and nuclear magnetic resonance spectroscopy. DFT calculations show that addition of the Criegee intermediate to the DMPO spin trap, leading to the formation of a six-membered ring adduct, occurs through a very favorable pathway and that the product is significantly more stable than the reactants, supporting the experimental characterization. A flow tube set up has been used to generate spin trap adducts with α-pinene CIs in the gas phase. We demonstrate that spin trap adducts with α-pinene CIs also form in the gas phase and that they are stable enough to be detected with online mass spectrometry. This new technique offers for the first time a method to characterize highly reactive and atmospherically relevant radical intermediates in situ.

Focally perfused succinate potentiates brain metabolism in head injury patients.

Following traumatic brain injury, complex cerebral energy perturbations occur. Correlating with unfavourable outcome, high brain extracellular lactate/pyruvate ratio suggests hypoxic metabolism and/or mitochondrial dysfunction. We investigated whether focal administration of succinate, a tricarboxylic acid cycle intermediate interacting directly with the mitochondrial electron transport chain, could improve cerebral metabolism. Microdialysis perfused disodium 2,3-13C2 succinate (12 mmol/L) for 24 h into nine sedated traumatic brain injury patients' brains, with simultaneous microdialysate collection for ISCUS analysis of energy metabolism biomarkers (nine patients) and nuclear magnetic resonance of 13C-labelled metabolites (six patients). Metabolites 2,3-13C2 malate and 2,3-13C2 glutamine indicated tricarboxylic acid cycle metabolism, and 2,3-13C2 lactate suggested tricarboxylic acid cycle spinout of pyruvate (by malic enzyme or phosphoenolpyruvate carboxykinase and pyruvate kinase), then lactate dehydrogenase-mediated conversion to lactate. Versus baseline, succinate perfusion significantly decreased lactate/pyruvate ratio (p = 0.015), mean difference -12%, due to increased pyruvate concentration (+17%); lactate changed little (-3%); concentrations decreased for glutamate (-43%) (p = 0.018) and glucose (-15%) (p = 0.038). Lower lactate/pyruvate ratio suggests better redox status: cytosolic NADH recycled to NAD+ by mitochondrial shuttles (malate-aspartate and/or glycerol 3-phosphate), diminishing lactate dehydrogenase-mediated pyruvate-to-lactate conversion, and lowering glutamate. Glucose decrease suggests improved utilisation. Direct tricarboxylic acid cycle supplementation with 2,3-13C2 succinate improved human traumatic brain injury brain chemistry, indicated by biomarkers and 13C-labelling patterns in metabolites.

Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-(13)C2 glucose.

Increased 'anaerobic' glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-(13)C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. (13)C enrichment for glycolytic 2,3-(13)C2 lactate was the median 5.4% (interquartile range (IQR) 4.6-7.5%) in TBI brain and 4.2% (2.4-4.4%) in 'normal' brain (P<0.01). The ratio of PPP-derived 3-(13)C lactate to glycolytic 2,3-(13)C2 lactate was median 4.9% (3.6-8.2%) in TBI brain and 6.7% (6.3-8.9%) in 'normal' brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=-0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than 'normal' brain. Several TBI patients exhibited PPP-lactate elevation above the 'normal' range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain.

(13)C-labelled microdialysis studies of cerebral metabolism in TBI patients.

Human brain chemistry is incompletely understood and better methodologies are needed. Traumatic brain injury (TBI) causes metabolic perturbations, one result of which includes increased brain lactate levels. Attention has largely focussed on glycolysis, whereby glucose is converted to pyruvate and lactate, and is proposed to act as an energy source by feeding into neurons' tricarboxylic acid (TCA) cycle, generating ATP. Also reportedly upregulated by TBI is the pentose phosphate pathway (PPP) that does not generate ATP but produces various molecules that are putatively neuroprotective, antioxidant and reparative, in addition to lactate among the end products. We have developed a novel combination of (13)C-labelled cerebral microdialysis both to deliver (13)C-labelled substrates into brains of TBI patients and recover the (13)C-labelled metabolites, with high-resolution (13)C NMR analysis of the microdialysates. This methodology has enabled us to achieve the first direct demonstration in humans that the brain can utilise lactate via the TCA cycle. We are currently using this methodology to make the first direct comparison of glycolysis and the PPP in human brain. In this article, we consider the application of (13)C-labelled cerebral microdialysis for studying brain energy metabolism in patients. We set this methodology within the context of metabolic pathways in the brain, and (13)C research modalities addressing them.

Rotamers or diastereomers? An overlooked NMR solution.

The existence of rotamers in a solution of analyte complicates (1)H NMR analysis, especially when the presence of diastereomers is also possible. Organic chemists have often responded to this problem by conducting variable-temperature (VT) NMR experiments, changing NMR solvents, or adding complexing agents. Here, with specific examples, we illustrate the use of simple yet widely overlooked chemical-exchange NMR experiments which allow the nonintrusive rapid distinguishment of rapidly equilibrating small molecules such as rotamers from nonequilibrating diastereomers.

The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study.

Energy metabolism in the human brain is not fully understood. Classically, glucose is regarded as the major energy substrate. However, lactate (conventionally a product of anaerobic metabolism) has been proposed to act as an energy source, yet whether this occurs in man is not known. Here we show that the human brain can indeed utilize lactate as an energy source via the tricarboxylic acid cycle. We used a novel combination of (13)C-labelled cerebral microdialysis both to deliver (13)C substrates into the brain and recover (13)C metabolites from the brain, and high-resolution (13)C nuclear magnetic resonance. Microdialysis catheters were placed in the vicinity of focal lesions and in relatively less injured regions of brain, in patients with traumatic brain injury. Infusion with 2-(13)C-acetate or 3-(13)C-lactate produced (13)C signals for glutamine C4, C3 and C2, indicating tricarboxylic acid cycle operation followed by conversion of glutamate to glutamine. This is the first direct demonstration of brain utilization of lactate as an energy source in humans.

Wound healing activity of acylated iridoid glycosides from Scrophularia nodosa.

Three acylated iridoid glycosides (E)-6-O-(2", 4"-diacetyl-3" -O-p-methoxycinnamoyl)-alpha-L-rhamnopyranosyl catalpol (scopolioside A) (1), (E)-6-O-(2"-acetyl-3", 4"-di-O,O-p-methoxycinnamoyl)-alpha-L-rhamnopyranosyl catalpol (scrophuloside A(4)) (2) and (E)-6-O-(2",3"-diacetyl-4"-O-p-methoxycinnamoyl)-alpha-L-rhamnopyranosyl catalpol (scrovalentinoside) (3) have been isolated from the dried seed pods of Scrophularia nodosa by HPLC. Their structures were determined by 1D and 2D NMR, UV/Vis and mass spectroscopy and by comparison with published data. All three compounds were shown in vitro to stimulate the growth of human dermal fibroblasts. The effect was negatively dose-dependent for 2 and 3 for which fibroblast growth stimulation was highest at 0.78 microg/mL but was not significantly different from the control at 100 microg/mL. The presence of these compounds in the mature seed pods may explain the ethnobotanical use of this plant in Europe for healing wounds.