Adolescent varicocele: Efficacy of indication-to-treat protocol and proposal of a grading system for postoperative hydroceles.

BACKGROUND: Varicocele is a common urologic anomaly in adolescent males; however, evidence-based treatment guidelines do not exist. Hydroceles are known to be a common complication after surgical therapy, with a wide variation in the reported incidence between 1 and 40%. AIM: This study aimed to introduce a standardized indication-to-treat protocol and prove its efficacy by analyzing the outcome of patients. Secondly, it aimed to better define postoperative hydroceles because the wide variation of reported incidence is attributed to a lack of definition. METHODS: Our standardized treatment protocol included an initial assessment with clinical grading of varicoceles, ultrasound evaluation of testicular volume, and calculation of the atrophy index. Indications for surgical treatment were testicular volume asymmetry >20%, discomfort and pain, or bilateral varicocele. The Palomo procedure (laparoscopically since 2005) was the standard procedure. Postoperative hydroceles were graded according to clinical findings and symptoms: Grade I, sonographic chance finding without clinical correlate; Grade II, palpable but clinically insignificant; Grade III, symptomatic. All patients treated according to the defined protocol were prospectively monitored between January 2001 and December 2015. RESULTS: A total of 129 patients with left varicocele were referred to our institution; 70 fulfilled the indication criteria for surgical treatment. Twenty-eight of these patients were treated for volume asymmetry, 26 of these showed catch-up growth. Forty-two patients were treated for discomfort and pain; the symptoms subsided in all of them. Postoperative hydroceles were detected in 36 patients (51%). In 29 patients this was a sonographic chance finding (Grade I). Three patients showed a palpable but clinically insignificant postoperative hydrocele (Grade II) and four patients (5.7%) showed symptomatic hydrocele (Grade III) where treatment was recommended. DISCUSSION: The treatment protocol allowed judicious indication for surgery and postoperative outcomes similar to previous reports. The high rate of catch-up growth in operated cases represents a proxy for successful treatment in cases where more precise parameters, like semen quality or paternity rate, were not yet detectable. The introduced grading system for postoperative hydroceles provs to be a valid and appropriate instrument, and promises to be a standardized method for comparing outcomes in future studies. CONCLUSION: The indication-to-treat protocol proved to be easily applicable, highly efficient, and have outcomes comparable to international literature. The necessity for a standardized grading of postoperative hydroceles was underscored in the data.

Antiphospholipid antibodies bind ATP: a putative mechanism for the pathogenesis of neuronal dysfunction.

Antiphospholipid antibodies (aPL) generated in experimental animals cross-react with ATP. We therefore examined the possibility that aPL IgG from human subjects bind to ATP by affinity column and an enzyme linked immunosorbent assay (ELISA). Sera with high levels of aPL IgG were collected from 12 patients with the antiphospholipid syndrome (APS). IgG fractions from 10 of 12 APS patients contained aPL that could be affinity-bound to an ATP column and completely eluted with NaCl 0.5 M. A significant (> 50%) inhibition of aPL IgG binding by ATP 5 mM was found in the majority. Similar inhibition was obtained with ADP but not with AMP or cAMP. All the affinity purified anti-ATP antibodies also bound beta2-glycoprotein-I (beta2-GPI, also known as apolipoprotein H) suggesting that, similar to most pathogenic aPL, their binding depends on this serum cofactor. We further investigated this possibility and found that the binding of beta2-GPI to the ATP column was similar to that of aPL IgG in that most was reversed by NaCl 0.5 M. Furthermore, addition of beta2-GPI to aPL IgG significantly increased the amount of aPL binding to an ATP column. We conclude that aPL IgG bind ATP, probably through beta32-GPI. This binding could interfere with the normal extracellular function of ATP and similar neurotransmitters.

Subunit specificity and mechanism of action of NMDA partial agonist D-cycloserine.

Recently, we have shown that 1-aminocyclopropanecarboxylic acid (ACPC) acts simultaneously as a high affinity full glycine agonist and a low affinity glutamate site competitive antagonist for NMDA receptor channels. In this paper, we have attempted to determine the subunit specificity and mechanism of action of a different putative cyclic partial agonist, D-cycloserine (DCS). NMDA receptor currents were measured utilizing the two-electrode voltage clamp technique on Xenopus oocytes injected with NR1-1a cRNA and either NR2A, NR2B or NR2C cRNA. Efficacies of DCS were 35-68% of glycine controls for channels containing NR1-1a and NR2A or NR2B subunits, but channels containing NR2C subunits had efficacies greater than glycine controls (192%). Unlike ACPC, DCS efficacy does not increase with increasing NMDA concentration; however, the lowered efficacy elicited by DCS results solely through its interaction with the glycine binding site. The efficacy of DCS was pH sensitive for NR2A or NR2B-containing channels, but not for channels containing NR2C. From this, we suggest that the protonated and deprotonated forms of DCS when bound, probably open NMDA channels with different efficiency. Two models compatible with these results are presented.

Desensitization of NMDA receptor channels is modulated by glutamate agonists.

Two distinct forms of desensitization have been characterized for N-methyl-D-aspartate (NMDA) receptors. One form results from a weakening of agonist affinity when channels are activated whereas the other form of desensitization results when channels enter a long-lived nonconducting state. A weakening of glycine affinity upon NMDA receptor activation has been reported. Cyclic reaction schemes for NMDA receptor activation require that a concomitant affinity shift should be observed for glutamate agonists. In this study, measurements of peak and steady-state NMDA receptor currents yielded EC50 values for glutamate that differed by 1.9-fold, but no differences were found for another agonist, L-cysteine-S-sulfate (LCSS). Simulations show that shifts in EC50 values may be masked by significant degrees of desensitization resulting from channels entering a long-lived nonconducting state. Simulations also show that a decrease in the degree of desensitization with increasing agonist concentration is a good indicator for the existence of desensitization resulting from a weakening of agonist affinity. Both glutamate and LCSS exhibited this trend. An affinity difference of three- to eightfold between high-and low-affinity agonist-binding states was estimated from fitting of dose-response data with models containing both types of desensitization. This indicates that activation of NMDA receptors causes a reduction in both glutamate and glycine affinities.

Antibodies to brain antigens following stroke.

Cerebral necrosis following stroke exposes brain antigens to the immune system, potentially initiating an antibody response. The authors measured levels of antibodies to specific neuronal antigens, neurofilaments (NF), and a ubiquitous antigen, cardiolipin (CL), in 45 patients following an acute first-ever stroke, within 48 hours, and 1, 3, and 6 months later. The mean levels of anti-NF antibodies were elevated compared with baseline at 1, 3, and 6, months (p = 0.012, 0.002, and 0.003 by paired t-test). Anti-CL levels did not change significantly.

From hand twister to mind twister: computer-aided treatment in traumatic wrist fracture.

OBJECTIVE: The use of computers as a treatment modality in the occupational therapy hand clinic is, as yet, not common practice. A computer interface for wrist movements was developed, and a study to justify the application of such a device is presented. METHOD: Forty-seven patients in a day hand clinic who had traumatic fracture of one hand with limitation of wrist mobility participated in the study. Participants were divided into two treatment groups: computer-aided treatment (high technology) and traditional brush machine treatment (low technology). A device was developed based on the brush machine in which the brush machine's mechanism was converted into a medial-lateral joystick. Right-to-left movements were digitally transformed for the use of a computer game. Participants were treated for 5 weeks, and outcome measures included range of motion (ROM), grip strength, edema, and level of interest. RESULTS: Results showed significant improvement in ROM, grip strength, and edema across 5 weeks for all participants. Although no significant differences were found between the two groups in ROM, grip strength, and edema, the computer-aided group showed significantly more interest in treatment than did the brush machine group. Finally, the interaction between treatment group and the attitude toward computers was not significant. CONCLUSIONS: These results indicate the potential for more interesting motor treatment and rehabilitation of the wrist through the use of computer games. The efficacy of using computers in occupational therapy clinics needs further investigation.

Antibodies to prothrombin in patients with Sneddon's syndrome.

Antiprothrombin antibodies (aPT), a new serologic marker of antiphospholipid syndrome, were studied in 46 patients randomly selected from 73 with Sneddon's syndrome and 20 matched normal controls. aPT were elevated in 26 patients (57%) and were not found in any of the controls. The addition of aPT data increased the proportion of Sneddon's syndrome patients with at least one type of antiphospholipid syndrome marker from 65 to 78%. The finding that aPT are common in Sneddon's syndrome supports the hypothesis that Sneddon's syndrome is a form of antiphospholipid syndrome.

Antineurofilament antibodies in postpolio syndrome.

We determined the levels of antineurofilament antibodies in 29 patients with postpolio syndrome (PPS), 26 stable postpolio (PP) patients, 22 patients with ALS, and 20 normal controls (NCs). Patients with PPS had higher antibody levels to cholinergic neurofilaments than did all other groups. PP patients and those with ALS had antibody levels similar to those of NCs. The antibody binding level showed no relation to the age of the patients, duration of disease, or motor score.

[Sneddon syndrome new clinical and immunological data]. / Novye klinicheskie i immunologocheskie dannye o sindrome Sneddona.

In 27 of 47 patients with Sneddon's syndrome (33 females, 14 males age 40 years) enzyme immunoassay has detected IgG-antibodies to prothrombin (aPT)--one of cofactor proteins responsible for binding of antiphospholipid antibodies (aPL) to phospholipids. Other aPL were also found: antibodies to cardiolipin (aCL), lupus anticoagulant (LA) in 14 and 27 patients, respectively. 37 (79%) patients had at least one of the studied aPL suggesting that such patients belong to patients with primary antiphospholipid syndrome. A correlation exists between aPT and LA: LA is detectable in 67% of aPT-positive patients compared to 45% of aPT-negative patients (p < 0.05). This is in agreement with the fact that prothrombin is a cofactor for most aPL registered as LA. Comparison of two subgroups of aPL patients different by dominant antigenic specificity (18 patients with aPT but free of ACL and 6 patients with aCP but free of aPT) demonstrated that the latter developed disorders of cerebral circulation, head ache, dementia and renal syndrome less frequently. aPT in Sneddon's syndrome seems to be a marker of comparatively low risk of thrombosis and less severe course of the disease.

Tolerance to the mydriatic effect of buprenorphine, butorphanol, nalbuphine, and cyclorphan, and cross-tolerance to morphine in mice.

An increase in the use of opioid derivatives in the treatment of pain syndrome in clinical practice, and especially in the treatment of cancer, has added impetus to the search for an agent which does not induce tolerance and cross-tolerance to other opiodis. The mydriatic effect of opioids in mice, the correlation between analgesia and mydriasis, and tolerance to the analgesic effect of morphine in mice were evaluated previously. In the present work, tolerance to the mydriatic effect of four agonist-antagonists and cross-tolerance to morphine were examined. Measurement of the pupillary diameter was performed using a binocular operating microscope. Tolerance and cross-tolerance to morphine were developed following a chronic use of buprenorphine, nalbuphine, and cyclorphan. After chronic injection of butorphanol, no tolerance or cross-tolerance to morphine was observed.

Interaction between antidepressants and phosphoinositide signal transduction system in human platelets.

The present study was designed to evaluate the inhibitory effect of antidepressants on thrombin-induced phosphoinositide (PI) hydrolysis. Thrombin 5 units/ml induced a 100%-200% increase in platelet inositol phosphates (IPs) formation. This effect was inhibited in a dose-dependent manner by various heterocyclic antidepressants (IC50 40-170 mumol/L) The monoamine oxidase inhibitor, phenelzine, in concentrations up to 500 mumol/L, was devoid of inhibitory activity. The tricyclic antidepressants, (50 mumol/L) inhibited also thrombin-induced platelet aggregation by 32%-47%. No alteration in thrombin-induced IPs formation was detected in recovered major depressed patients (n = 15) maintained on clomipramine (75-150 mg/day). These results indicate that the heterocyclic antidepressants interfere with the thrombin-linked PI-signaling system. However, the inhibitory effect is achieved only in concentrations above the plasma concentrations obtained with therapeutic doses of these agents.

The pupillary effects of retrobulbar injection of botulinum toxin A (oculinum) in albino rats.

Botulinum toxin (BoTx) has been clinically used in the treatment of localized dystonic states such as blepharospasm, as well as in strabismus. Reported side effects have included primary excessive weakness of neighboring extraocular muscles. To evaluate possible involvement of the iris, we injected BoTx into the retrobular space of albino rats. Ipsilateral mydriasis with cholinomimetic supersensitivity developed in the treated animals. There was no apparent optic nerve dysfunction. The authors observed these effects using BoTx doses insufficient to cause clinical weakness or electrophysiological evidence of generalized neuromuscular dysfunction. The mydriasis disappeared spontaneously within 2-3 weeks. Higher BoTx doses resulted in severe neuromuscular paralysis and death. These findings were consistent with clinical botulism, which may include autonomic paralysis. The site of BoTx action could be the ciliary ganglion or cholinergic terminals in the iris. The authors concluded that side effects of BoTx were not necessarily limited to striated muscle weakness.

Sympathomimetic amines and cardiac arrhythmias.

STUDY OBJECTIVE: The aim was to investigate the arrhythmogenic properties of several sympathomimetic amines and their antagonism by adrenergic blocking drugs. DESIGN: Arrhythmia was induced by the investigated drugs, injected intravenously: adrenaline (ADR); noradrenaline (NA); phenylephrine (PE); isoprenaline (IP); terbutaline (Tb) and salbutamol (Sb). ADR and PE were also tested for their arrhythmogenic properties after the administration of the adrenergic antagonists propranolol, phentolamine, or both. The dose required to induce arrhythmia and the proportion of animals that developed arrhythmia at a given dose were recorded. SUBJECTS: 63 anaesthetised cats of either sex, weight 2.0-4.3 kg, were used. MEASUREMENTS AND RESULTS: The electrocardiogram was recorded continuously. The arrhythmogenic potency sequence (expressed as arrhythmogenic dose, AD50 in micrograms) was: ADR 16; NA 24; PE 75; IP 133; Tb 500; Sb greater than 1000. The arrhythmogenic efficacy (in %) was: ADR 97; NA 91; PE 90; IP 82; Tb 50; and Sb 0. Propranolol and phentolamine were both effective in reducing the arrhythmogenic effects of ADR and PE. However, their combined administration was most effective and abolished the arrhythmias. CONCLUSIONS: Arrhythmogenicity is a property of sympathomimetic amines with either alpha or beta adrenergic effects, but simultaneous activation of both types of receptors is required for maximal manifestations. Similarly, antagonism at both sites is necessary in order to abolish arrhythmias induced by sympathomimetic amines completely.

Nicotine mydriasis.

In mice, nicotine produces dose-dependent mydriasis following interperitoneal or intracerebroventicular administration but not after local application through the conjunctival sac. Since mydriasis is not prevented by cervical sympathectomy, it is likely to be due to central inhibition of the parasympathetic tone. Repeated administration of nicotine over 8 h progressively diminished and finally obliterated the response to a test dose of nicotine. This acute tolerance was maintained for 24 h. Tolerance was also produced by daily administration of nicotine and lasted up to 12 days after withdrawal. The easily measurable examination of the pupillary responses provide a convenient method for the investigation of mechanisms underlying tolerance to nicotine.

Cardiac denervation supersensitivity produced in guinea pigs by 6-hydroxy-dopamine.

The effects of chemical sympathectomy with 6-hydroxydopamine (6-OH-DA) on the sensitivity of guinea-pig heart to catecholamines were studied. Heart rate at rest and chronotropic effects of catecholamines remained unchanged after chemical sympathectomy, while the arrhythmogenic effects of epinephrine, norepinephrine and isoprenaline were potentiated markedly. Our results indicate that chemical sympathectomy with 6-OH-DA produced post synaptic denervation supersensitivity in the heart ventricles.

Agonist interaction and decentralization supersensitivity in the nictitating membrane of the cat.

1. The responses to individual drugs and to combinations of two drugs were studied in normal and chronically decentralized nictitating membranes (NM) of cats. Noradrenaline (NA), acetylcholine (ACh), serotonin (5HT) and potassium chloride (KCl) and the combinations NA + ACh, NA + 5HT, NA + KCl and ACh + 5HT were injected intra-arterially towards the smooth muscle. 2. Chronic decentralization resulted in supersensitivity to each of these agonists when injected alone. 3. The contraction of the normal NM caused by each drug combination showed potentiation in comparison to the sum of contractions caused by the same drugs given separately. The same drug combinations showed no potentiation in decentralized muscle. 4. Decentralization supersensitivity and potentiation due to agonist interactions in normal preparations may share a common mechanism. The involvement of calcium in this phenomenon is discussed.

The chick as a model for malignant hyperpyrexia.

Administration of succinylcholine (SCh) to chicks produces rigid paralysis and death due to respiratory impairment. The mechanism of the SCh effect is probably related to the multiple innervation of muscle fibres, leading to excessive intracellular accumulation of calcium. This situation may be similar to that in malignant hyperpyrexia (MH) occurring in mammals. Dantrolene sodium, phenytoin and procain, drugs used against MH, were found to afford protection against SCh rigidity and death in chicks. It is suggested that the chick can be used as a convenient model for rapid screening of drugs potentially active against NH.

Prolongation of responses in decentralization supersensitivity.

In chronically decentralized nictitating membranes of cats the responses to norepinephrine and to acetylcholine were markedly prolonged. The increased duration was not directly related to the increased amplitude of the contractions. It is likely to be due to a change of the muscle itself.