Orchestration of occludins, claudins, catenins and cadherins as players involved in maintenance of the blood-epididymal barrier in animals and humans

Although spermatozoa are formed during spermatogenesis in the testis, testicular spermatozoa are immature and cannot swim or fertilize. These critical spermatozoal functions are acquired in the epididymis where a specific luminal environment is created by the blood-epididymal barrier; proteins secreted by epididymal principal cells bind to maturing spermatozoa and regulate the maturational process of the spermatozoa. In the epididymis, epithelial cell-cell interactions are mediated by adhering junctions, necessary for cell adhesion, and by tight junctions, which form the blood-epididymal barrier. The regulation of these cellular junctions is thought to represent a key determinant in the process of sperm maturation within the epididymis. Tight junctions between adjacent principal cells permit the formation of a specific microenvironment in the lumen of the epididymis that is essential for sperm maturation. Although we have made significant progress in understanding epididymal function and the blood-epididymal barrier, using animal models, there is limited information on the human epididymis. If we are to understand the normal and pathological conditions attributable to human epididymal function, we must clearly establish the physiological, cellular and molecular regulation of the human epididymis, develop tools to characterize these functions and develop clinical strategies that will use epididymal functions to improve treatment of infertility. （Asian J Androl 2007 July; 9： 463- 475）     

Ethical issues in the initiation and termination of treatment

This report addresses the ethical issues involved in decisions to initiate and terminate treatment. A general framework is constructed and then two illustrative cases are discussed. The framework is developed in three stages. First, the issue of guiding ethical principles is examined, with a multiple-principle approach being adopted. Second, common models of the care-giver/patient relationship (warrior, parental, contractual, covenantal) are identified, and their varying impacts on treatment decisions are explained and assessed. Third, specific criteria for determining when to initiate and terminate treatment are introduced. Two criteria (willingness and medical benefit) are commended in the context of initiating treatment, while three distinctions (willing v unwilling, passive v active, and terminal v nonterminal) are found to be particularly helpful when deciding if treatment should be terminated. Two illustrative cases involve end-stage renal disease (ESRD). The first describes a noncompliant and abusive intravenous (IV) drug user on hemodialysis who wants to continue on dialysis and eventually receive a living-related donor kidney transplant. The second describes a patient's decisions to refuse feeding gastrostomy and jejunostomy, any further surgical or diagnostic intervention, and eventually dialysis-though only after a period of time when he wants dialysis alone to continue.     

The eck fistula in animals and humans

In all species so far studied, including man, portacaval shunt causes the same changes in liver morphology, including hepatocyte atrophy, fatty infiltration, deglycogenation, depletion and disorganization of the rough endoplasmic reticulum (RER) and its lining polyribosomes, and variable but less specific damage to other organelles. Many, perhaps all, biosynthetic processes are quickly depressed, largely secondary to the selective damage to the RER, which is the "factory" of the cell. These structural and metabolic changes in the liver after portal diversion are caused by the diversion around the liver of the hepatotrophic substances in portal venous blood, of which endogenous insulin is the most important. In experimental animals, the injury of Eck's fistula can be prevented by infusing insulin into the tied-off hilar portal vein. The subtle but far-reaching changes in hepatic function after portal diversion have made it possible to use this procedure in palliating three inborn errors of metabolism: glycogen storage disease, familial hypercholesterolemia, and alpha 1-antitrypsin deficiency. In these three diseases, the abnormalities caused by portal diversion have counteracted abnormalities in the patients that were caused by the inborn errors. In these diseases, amelioration of the inborn errors depends on the completeness of the portal diversion. In contrast, total portal diversion to treat complications of portal hypertension is undesirable and always will degrade hepatic function if a significant amount of hepatopetal portal venous blood is taken from the liver. When total portal diversion is achieved (and this is to be expected after all conventional shunts), the incidence of hepatic failure and hepatic encephalopathy is increased. If portal diversion must be done for the control of variceal hemorrhage, a selective procedure such as the Warren procedure is theoretically superior to the completely diverting shunt. In practice, better patient survival has not been achieved after selective shunts than after conventional shunts, but the incidence of hepatic encephalopathy has been less.     

Solvent nephrotoxicity in humans and experimental animals

Evidence from human case reports, epidemiologic studies and animal experiments have suggested that exposure to organic solvents is associated with a wide spectrum of renal disorders, including tubular necrosis, interstitial disease, glomerulonephritis and neoplasia. This review summarizes what is known about solvent-induced renal damage in humans and experimental animals, with emphasis on hypothesized mechanisms by which this broad range of disorders may occur.     

Paternal transmission of genetic damage: findings in animals and humans

The concept that mutations can be induced in the male germ-line and result in adverse effects in the offspring has achieved only limited acceptance despite considerable theoretical appeal. This is partly because fetal malformations are generally perceived to be induced solely as a result of maternally mediated events during gestation and partly because the low incidence of the end-points concerned make experimental approaches costly and time-consuming. Nonetheless, a substantial body of work relating to the hypothesis has accumulated in the last 20 years, which has never been reviewed in its entirety. A consideration of the available evidence indicates that preconceptional paternal exposure to mutagens (particularly radiation, cyclophosphamide and ethylnitrosourea) can indeed, under certain conditions, have adverse effects on offspring. The results suggest two principal mechanisms by which such effects may be induced: the induction of germ-line genomic instability or the suppression of germ cell apoptosis.     

Whole blood platelet aggregation in humans and animals: a comparative study

BACKGROUND. Many animal species are used to evaluate the performance and blood compatibility of cardiovascular devices, but interspecies differences in platelet activity have not been well characterized. This study measures platelet response to six agonists in human, dog, and calf blood. MATERIALS AND METHODS. We used whole blood impedance lumi-aggregometry to measure platelet aggregation and ATP release in blood samples from adult humans (n = 19), mongrel dogs (n = 19), and Holstein calves (n = 7). The agonists were collagen, ristocetin, arachidonic acid, thrombin, and three concentrations of both ADP and epinephrine. RESULTS. Only collagen (1 microg/ml) and ADP (5, 10, and 20 microM) caused aggregation and ATP release in all samples. Canine platelets responded to all six agonists at all doses. Human platelets responded to everything except epinephrine at 2 and 100 microM. Bovine platelets responded only to collagen, ADP, and thrombin. In bovine platelets, aggregation from collagen and ATP release from thrombin were significantly lower than the corresponding responses in human and canine blood. The aggregation induced by 10 microM ADP was significantly higher in canine than in human platelets. CONCLUSION. Human, canine, and bovine platelets have very different responses to agonists. In these models, collagen (1 microg/ml) and ADP (10 microM) are the agonists of choice for investigating whole blood platelet aggregation because they provide the most consistent results between species. For ATP release, 1 U/ml thrombin is the recommended agonist and the dose for all three species.     

Taxonomy of Ochroconis,genus including opportunistic pathogens on humans and animals

The genus Ochroconis (Sympoventuriaceae, Venturiales) is revised and currently contains 13 species for which the phylogenetic position has been determined using multilocus sequencing. The older generic name Scolecobasidium is considered to be of doubtful identity because the type specimen is ambiguous. Within the Ochroconis lineage, phylogenetic distances of all markers analyzed are exceptionally large, both between and within species. A new genus Verruconis is proposed for the neurotropic opportunist Ochroconis gallopava. Species accepted within the lineages are keyed out on the basis of phenotypic characters. Main ecological traits within each species are discussed. Verruconis species are thermophilic and one of them is an important agent of infection in the brain, while Ochroconis is mesophilic, several species causing infections in cold-blooded animals.     

Decision making for the initiation and termination of dialysis in patients with advanced cancer

Age is a risk factor for both cancer and end‐stage renal disease (ESRD). Newer cancer treatments are allowing patients to live longer with their cancer, the renal toxicity from the cancer itself or from the therapies that was used to treat the malignancy. Consequently, nephrologists will increasingly be asked to evaluate and counsel patients with ESRD and advanced cancer regarding the initiation of dialysis. Data on morbidity, mortality, and quality of life (QOL) outcomes in this population are sparse. Expectations regarding what dialysis can reasonably accomplish in this cohort can be unrealistically high among patients, their family members and the rest of the health care team. This article will discuss some results from the available studies on mortality and QOL outcomes in this cohort and advise the nephrologist about how to approach these challenging discussions.     

Clinical and experimental findings in humans and animals with chemotherapy-induced peripheral neuropathy

Pain arises from numerous causes in cancer patients. Well known to cancer care providers, but perhaps less well so to others, is that the main causes of pain in cancer patients in fact arise due to cancer treatments more so than the disease itself. In this paper clinical and laboratory findings on the characteristics of chemotherapy-induced neuropathic pain are reviewed and a scheme for the underlying mechanisms is outlined.     

Sensitivity and specificity of somatosensory and neurogenic-motor evoked potentials in animals and humans

The purpose of this study was to report the effects of spinal cord compression, ischemia, and distraction on clinical status, and somatosensory (SEP) and neurogenic-motor evoked potentials (NMEPs) in animals. The authors also reported their clinical experience with NMEPs elicited from humans undergoing surgery for spinal deformities. Results from the animal studies indicate that NMEPs are more sensitive and specific to the effects from spinal cord compression, ischemia, and distraction than SEPs. In every situation, NMEPs always correlated with the animal's post-surgical clinical status, while SEPs demonstrated an unacceptable false positive and false negative rate. In the 111 clinical cases in which NMEPs were administered, reliable NMEPs were easily elicited in more than 90% of the cases. In the remaining cases, no reliable NMEPs could be recorded because of procedural errors, which have been resolved. The results from this study suggest that the use of NMEPs should be considered as an adjunct to SEPs when monitoring spinal cord function during surgery.     

Interrelations between macroorganisms and bacteria in wounds and tissues of humans and animals

It is shown that bacteria from the gastrointestinal tract penetrate systematically into the tissues of the focus of damage in man and animals in the blood and lymph. It was found that certain bacterial species maintain vitality in tissues, in which they do not induce pathological reactions but may produce a therapeutic effect due to the production of antibiotics, proteolytic enzymes, immunomodulators, etc. The author describes the results of experimental and clinical study of Sporobacterin, a new agent, intended for the prevention and treatment of surgical infection.     

Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans

Glucose is freely filtered in the glomeruli before being almost entirely reabsorbed into circulation from the proximal renal tubules. The sodium-glucose cotransporter 2 (SGLT2), present in the S1 segment of the proximal tubule, is responsible for the majority of glucose reabsorption. SGLT2 inhibitors reduce glucose reabsorption and increase urinary glucose excretion. In animal models and humans with type 2 diabetes, this effect is associated with reduced fasting and postprandial blood glucose levels, and reduced hemoglobin A1c. Animal studies suggest that reduction of hyperglycemia with SGLT2 inhibitors may also improve insulin sensitivity and preserve β-cell function. Urinary excretion of excess calories with SGLT2 inhibitors is also associated with reduction in body weight. Modest reductions in blood pressure have been noted with SGLT2 inhibitors, consistent with a mild diuretic action. Some C-glucoside SGLT2 inhibitors, such as dapagliflozin, have pharmacokinetic properties that make them amenable to once-daily dosing.     

Silver resistance in MRSA isolated from wound and nasal sources in humans and animals

Methicillin‐resistant Staphylococcusaureus (MRSA) colonises skin, nasal passages and dermal wounds. Methods used to manage wounds infected and colonised with MRSA often include the use of topical antiseptics such as ionic silver and iodine. The objectives of this study were to determine the prevalence of silver‐resistance (sil) genes in MRSA and methicillin‐resistant coagulase‐negative staphylococci (MR‐CNS) isolated from wounds and nasal cavities of humans and animals, and also to determine the susceptibility of sil‐positive and sil‐negative MRSA isolates to a silver‐containing Hydrofiber^® (SCH) wound dressing, on planktonic silE‐positive and silE‐negative MRSA. Polymerase chain reaction was used to determine the presence of three silver‐resistance (sil) genes, silE, silP and silS in 33 MRSA and 8 methicillin‐resistant staphylococci (MR‐CNS). SilP and silS genes were absent in all isolates tested; however, two MRSA strains were found to contain the silE gene, together with one isolate of MR‐CNS. Phenotypic resistance of the silE‐positive strains and their susceptibility to the SCH dressing was evaluated using the zone of inhibition test on Mueller Hinton agar, and confocal laser microscopy using a live/dead fluorescent stain. Results confirmed that the SCH dressing was effective in killing all MRSA strains with and without the silE gene. First, this study showed that the prevalence of sil genes was low in the isolates investigated; and secondly, that the presence of a silver‐resistance gene (silE) in MRSA and MR‐CNS did not afford protection to the organism in the presence of a SCH wound dressing. The use of topical antiseptics in chronic wound care should be considered before the use of antibiotics that can result in their overuse and the risk of further resistance.     

Opioid therapy for chronic noncancer pain: practice guidelines for initiation and maintenance of therapy

Contemporary standard pharmacological care for the treatment of noncancer pain includes the use of opioid medications. The responsiveness of neuropathic pain to opioids has long been an area of controversy. Evidence from multiple randomized controlled trials indicates that opioids can relieve pain in a variety of neuropathic pain syndromes. Opioids are typically reserved for moderate to severe pain that cannot be relieved by the nonsteroidal anti-inflammatory drugs (NSAIDs). Opioids are often used in combination with other adjuvants or other analgesic agents. The advantage of opioids is the lack of a ceiling effect of the pure mu opioid agonists. The disadvantages of these drugs are a series of mechanism-based opioids-related side effects (e.g., nausea, drowsiness, constipation) and the potential issue of their abuse and misuse. Each patient needs to undergo a comprehensive evaluation and receive education on the treatment. The physician must be well conversant with the differential diagnosis and definitions of physical dependence, tolerance, pseudotolerance, aberrant behaviors, addiction, and pseudoaddiction. No specific opioid drug is intrinsically 'better' than the others. Opioid rotation refers to the switch from one opioid to another when the degree of analgesia obtained is limited by the persistence of adverse effects or the occurrence of clinically relevant tolerance. This approach is based on the observation that a patient's response varies from opioid to opioid. At present, after 1) appropriate selection of patients and 2) longitudinal patient care with routine assessment of degree of analgesia, functional daily activities, adverse events and aberrant behaviors is carried out, opioid therapy can be the safest and most effective treatment measure for quality of life improvement in the chronic pain patient.     

Influence of initiation of maintenance hemodialysis on biomarkers of inflammation and oxidative stress

BACKGROUND: Chronic inflammation and oxidative stress are highly prevalent in patients with chronic kidney disease and end-stage renal disease (ESRD). These conditions contribute to high mortality rates associated with cardiovascular disease, the leading cause of death in this patient population. To our knowledge, no prospective studies have examined how initiation of maintenance hemodialysis (MHD) affects biomarkers of inflammation and oxidative stress status. METHODS: This was a prospective cohort study evaluating time-dependent changes in C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), and protein carbonyl content before and after initiation of MHD over a 12-month period. Fifty incident hemodialysis patients [57.6 +/- 17.2 years, 60% male, 38% Caucasians, 32% insulin-dependent diabetes mellitus (IDDM) were studied, with 50 healthy subjects for comparison. The study variables were assessed before the initial outpatient hemodialysis treatment, and every 3 months thereafter for 12 months. RESULTS: At baseline, CRP, IL-6, and carbonyl content levels were significantly higher in MHD patients compared with healthy subjects (P < 0.001 for each). After initiation of MHD, there were no significant changes in any of the study variables. Patients who initiated MHD with the highest levels of all the study variables had a significant decrease over the next year, but the variables were still higher than normal at the end of the 12-month study period. CONCLUSION: Our data show that initiation of MHD does not have significant influence on plasma concentrations of CRP, IL-6, and IL-10, as well as plasma protein carbonyl content. These findings suggest that MHD is ineffective in controlling inflammation and oxidative stress in uremia.     

A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circulates in blood at levels that increase during prolonged fasting in rats. When administered to rodents at supraphysiological doses, ghrelin activates hypothalamic neuropeptide Y/agouti gene-related protein neurons and increases food intake and body weight. These findings suggest that ghrelin may participate in meal initiation. As a first step to investigate this hypothesis, we sought to determine whether circulating ghrelin levels are elevated before the consumption of individual meals in humans. Ghrelin, insulin, and leptin were measured by radioimmunoassay in plasma samples drawn 38 times throughout a 24-h period in 10 healthy subjects provided meals on a fixed schedule. Plasma ghrelin levels increased nearly twofold immediately before each meal and fell to trough levels within 1 h after eating, a pattern reciprocal to that of insulin. Intermeal ghrelin levels displayed a diurnal rhythm that was exactly in phase with that of leptin, with both hormones rising throughout the day to a zenith at 0100, then falling overnight to a nadir at 0900. Ghrelin levels sampled during the troughs before and after breakfast correlated strongly with 24-h integrated area under the curve values (r = 0.873 and 0.954, respectively), suggesting that these convenient, single measurements might serve as surrogates for 24-h profiles to estimate overall ghrelin levels. Circulating ghrelin also correlated positively with age (r = 0.701). The clear preprandial rise and postprandial fall in plasma ghrelin levels support the hypothesis that ghrelin plays a physiological role in meal initiation in humans.