[A role of genetic factors and related disorder of the folate cycle in ischemic stroke]. / Rol' geneticheskikh faktorov i svyazannykh s nimi narushenii folatnogo tsikla v razvitii ishemicheskogo insul'ta.

AIM: To study a role of MTHFR mutations and their associations with the disturbances of basic parameters of the folate cycle in the development of ischemic stroke (IS). MATERIAL AND METHODS: Fifty-one post-stroke patients, 26 women and 25 men, aged from 29 to 87 years, were included in the study. The control group consisted of 47 healthy people, 23 women and 24 men, aged from 30 to 83 years. MTHFR: rs1801131 and rs1801133 polymorphisms were genotyped. Contents of folate, B12 and homocysteine were measured. RESULTS: The risk group which was characterized by the presence of risk variants of rs1801131 and rs1801133 polymorphisms, changes in the parameters of the folate cycle (the decrease in B12 concentration (≤500 pg/ml)) in the combination with hyperhomocysteinemia (≥13 mcmol/L) was identified. CONCLUSION: The disturbance of the folate cycle, including gene variations, is a basic pathogenetic link in the development of cerebral atherosclerosis and associated cerebrovascular diseases.

Use of a Bone Graft Drill Harvester to Create the Fenestration During Arthroscopic Ulnohumeral Arthroplasty.

The Outerbridge-Kashiwagi procedure, or ulnohumeral arthroplasty, was described in 1978 as a method of treating elbow arthritis by creating a fenestration in the olecranon fossa. This fenestration diminishes the likelihood of recurrent spurs in the olecranon fossa and coronoid fossa, without loss of structural bony strength. Arthroscopic techniques have now been developed to perform this procedure. We describe an efficient method of creating the fenestration between the olecranon fossa and coronoid fossa during an arthroscopic ulnohumeral arthroplasty, or Outerbridge-Kashiwagi procedure, that also reduces the amount of residual bone debris produced during the resection.

ERK-regulated αB-crystallin induction by matrix detachment inhibits anoikis and promotes lung metastasis in vivo.

Evasion of extracellular matrix detachment-induced apoptosis ('anoikis') is a defining characteristic of metastatic tumor cells. The ability of metastatic carcinoma cells to survive matrix detachment and escape anoikis enables them to disseminate as viable circulating tumor cells and seed distant organs. Here we report that αB-crystallin, an antiapoptotic molecular chaperone implicated in the pathogenesis of diverse poor-prognosis solid tumors, is induced by matrix detachment and confers anoikis resistance. Specifically, we demonstrate that matrix detachment downregulates extracellular signal-regulated kinase (ERK) activity and increases αB-crystallin protein and messenger RNA (mRNA) levels. Moreover, we show that ERK inhibition in adherent cancer cells mimics matrix detachment by increasing αB-crystallin protein and mRNA levels, whereas constitutive ERK activation suppresses αB-crystallin induction during matrix detachment. These findings indicate that ERK inhibition is both necessary and sufficient for αB-crystallin induction by matrix detachment. To examine the functional consequences of αB-crystallin induction in anoikis, we stably silenced αB-crystallin in two different metastatic carcinoma cell lines. Strikingly, silencing αB-crystallin increased matrix detachment-induced caspase activation and apoptosis but did not affect cell viability of adherent cancer cells. In addition, silencing αB-crystallin in metastatic carcinoma cells reduced the number of viable circulating tumor cells and inhibited lung metastasis in two orthotopic models, but had little or no effect on primary tumor growth. Taken together, our findings point to αB-crystallin as a novel regulator of anoikis resistance that is induced by matrix detachment-mediated suppression of ERK signaling and promotes lung metastasis. Our results also suggest that αB-crystallin represents a promising molecular target for antimetastatic therapies.

Four-dimensional computed tomography scans facilitate preoperative planning in snapping scapula syndrome.

HYPOTHESIS: Because a 4-dimensional CT scan (4D CT) is able to provide a moving 3-dimensional (3D) image in real time in patients with snapping scapula syndrome, a 4D CT scan should be able to demonstrate bony impingement of the scapula on the posterior thorax. This study was performed to determine if 4D CT scans aid the clinician in defining the size and location of the scapular bone causing impingement in patients with snapping scapula syndrome. MATERIALS AND METHODS: Between October 2009 and August 2013, 12 patients (median age, 26.5 years; range 15-55 years) with snapping scapula syndrome were investigated with 4D CT. The images formed produced a dynamic volume-rendered reconstruction of the scapulothoracic joint that displayed its movements and any dynamic area of impingement of the scapula on surrounding bony structures. Asymmetry between symptomatic and asymptomatic scapulae was used to determine the radiologic cause of the patient's symptoms. After the failure of conservative management, 8 patients underwent surgery for their condition. RESULTS: Five patients demonstrated bony contact of the scapula on the posterior thoracic ribs. Four patients demonstrated no bony contact but close apposition of the scapula to the posterior thoracic ribs. Three patients demonstrated no bony impingement but abnormal movement of the second and third rib caused by a soft-tissue tethering structure. CONCLUSION: The 4D CT scan images defined pathology well in patients with snapping scapula syndrome and improved assessment of the amount and location of the scapular bone and soft tissue causing symptoms.

The danger zone for the plantar and calcaneal divisions of the tibial nerve - a cadaveric study

In this anatomical, cadaveric study we describe a novel method of determining the point of origin of the plantar and calcaneal divisions of the tibial nerve around the tarsal tunnel, in the clinical setting, without requiring the exact path of the nerve to be known. To this end, we describe an area that arises from the midpoint of the navicular-calcaneal line (MP-NCL), which contains both nerve divisions in the majority of cases. We called this area the danger zone. We identified the size and location of this danger zone by dissecting a total of 50 cadaveric feet. We measured the distance from the origin of each nerve division to both the navicular tuberosity and the calcaneal insertion of the Achilles tendon. From these measurements we were able to calculate the distance of each division from the MP-NCL along two axes, the navicular-calcaneal line (NCL) and a line perpendicular to this crossing at the midpoint. The danger zone of the tibial nerve, around the tarsal tunnel is a 16.5 cm² (5.9 x 2.8 cm) quadrilateral area that passes posterior and proximal from the MP-NCL. This area in our study contained both the plantar and calcaneal divisions of the posterior tibial nerve in 82% of cases. Those divisions that arose outside this area (18%) occurred up to 0.5 cm anterior to the MP-NCL and 1.4 cm distal to the NCL

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Synovial chondromatosis affecting a digital proximal interphalangeal joint.

We present a case of synovial chondromatosis affecting the interphalangeal joint where the disease did not clearly manifest itself on pre-operative radiographs. Although rare, surgeons should consider articular synovial chondromatosis as a differential for pain and stiffness in any joint, even those of the hand.

The use of four-dimensional computed tomography to diagnose costoclavicular impingement causing thoracic outlet syndrome.

Thoracic outlet syndrome is caused by compression of the neurovascular structures crossing the interscalene triangle, costoclavicular space or retropectoralis minor space. The costoclavicular space is the most frequent site of arterial compression and is mainly a result of anatomical variations and masses occupying the costoclavicular space causing a compression effect on the vascular or neural structures within it. We present a case of thoracic outlet syndrome caused by dynamic impingement of the clavicle and the second rib diagnosed by four-dimensional computed tomography scanning.

Inhibition of monoamine oxidase isoforms modulates nicotine withdrawal syndrome in the rat.

AIMS: There have been many reports of monoamine oxidase (MAO) inhibition by non-nicotine ingredients in tobacco smoke, persisting for days after smoking cessation. This study determined the effect of inhibiting MAO and its isoforms on nicotine withdrawal syndrome. MAIN METHODS: Rats were rendered nicotine-dependent by seven days of subcutaneous (s.c.) 9 mg/kg/day infusion of nicotine bitartrate. Twenty-two hours after termination of infusion, they were observed over 20 min for somatically expressed nicotine withdrawal signs. Three hours before observation, rats were injected intraperitoneally (i.p.) with 4 mg/kg each of the MAO A antagonist clorgyline and the MAO B antagonist deprenyl, or with saline alone. A similar experiment was performed with non-dependent, saline-infused rats. Another experiment compared nicotine-dependent rats that received injections of either saline or 4 mg/kg clorgyline alone. A further experiment compared rats receiving either saline or 4 mg/kg deprenyl alone. KEY FINDINGS: Combined treatment with both MAO inhibitors markedly and significantly exacerbated somatically expressed nicotine withdrawal signs in nicotine infused rats, while having no significant effects in saline-infused rats. Rats injected s.c. with 4 mg/kg clorgyline alone had significantly more withdrawal signs than saline-injected rats, while deprenyl-injected rats had significantly fewer signs than saline controls. Assays confirmed that clorgyline thoroughly reduced MAO A enzymatic activity and deprenyl thoroughly reduced MAO B activity. SIGNIFICANCE: The results suggest that inhibition of MAO A may contribute to the intensity of withdrawal syndrome in smoking cessation.

Novel assessment of the sternoclavicular joint with computed tomography for planning interventional approach.

OBJECTIVES: To describe the plane of the sternoclavicular joint (SCJ) to aid planning of instrument orientation during invasive procedures. METHODS: Computed tomography (CT) images of 80 consecutive patients aged 25 to 40 years with appropriate chest imaging series were retrospectively reviewed. Patients with a previous median sternotomy, fused manubriosternal joint or fracture were excluded. The medial clavicle was found to vary greatly in its anatomy such that a representative morphology could not be described. The manubrium was found to be a more consistent structure and was examined in more detail. The angulation of the SCJ was measured in three orthogonal planes using CT multiplanar reformats. Each SCJ (160 in total) was assessed for transverse, coronal, and sagittal angulation of the central manubrial articular surface in respect to the long axis of the manubrial body using a newly devised measurement technique. RESULTS: The mean angles (± standard deviation) of the SCJs were 62.4 ± 9.7° to the transverse plane, 149.3 ± 7.3° to the coronal plane and 69.8 ± 7.5 to the sagittal plane. There was no significant difference in transverse (p = 0.41) or sagittal (p = 0.60) angulation between sides, however there was a significant difference for the coronal plane (p = 0.04). No significant differences were noted between the sexes in any plane. CONCLUSIONS: Increasing use of invasive diagnostic and treatment techniques dictate that a safe approach to the joint should be used to reduce the risk of iatrogenic injury. This study adds to existing knowledge of SCJ anatomy and its variation within the population. Understanding this can minimize the risk to adjacent structures when approaching the SCJ with injection needles or arthroscopic instruments.

Conservative management of Dieterich disease: case report.

Dieterich disease is characterized by avascular necrosis of the metacarpal head. The recent literature has described surgical management of this condition relatively soon after its presentation. We present a case treated conservatively with a satisfactory outcome at 28 months.

[Investigation of the new QNR-based mechanism of quinolone resistance among enterobacterial strains isolated in Henri-Mondor hospital 2002-2005]. / Emergence et diffusion chez les entérobactéries du nouveau mécanisme de résistance plasmidique aux quinolones Qnr (résultats hôpital Henri-Mondor 2002-2005).

AIM OF THE STUDY: To assess the prevalence of the novel plasmid-mediated resistance to quinolones in enterobacteria isolated in our hospital. MATERIALS AND METHODS: We have screened 737 enterobacterial strains isolated in Henri-Mondor hospital between 2002 and 2005 for the presence of the qnr gene by PCR using specific primers. Among them, 282 had a phenotype in concordance with extended spectrum betalactamase (ESBL). Qnr-positive strains were phenotypically and genetically characterized, and epidemiological link between the cases was investigated. RESULTS: Five qnr+ strains were described. The global prevalence was 0.7% but 5/282 among ESBL producing strains and 0/437 among quinolone-resistant enterobacteria non producing ESBL. The sequences of the PCR products were identical to qnrA in the environment of the integron In36. All the strains harboured also the ESBL SHV-12 gene. Transfer of qnr by conjugation raised quinolone MICs from 2 to 24 times. However clinical strains harboured a higher level of quinolone resistance and harboured also DNA gyrase and topoisomerase IV mutations. Two strains were epidemiologically related by molecular typing and contact tracing revealed that the patients have been previously hospitalized in the same tertiary care center. CONCLUSION: We described the first investigation of qnr-positive strains in one hospital in France over 4 years. Although the qnr gene prevalence is low, nosocomial transmission is already shown and the transfer of the qnr containing integron among ESBL producing strains may predict future epidemic. Surveillance will be necessary to confirm this low prevalence rate of qnr in France.

Hippocampal injections of amyloid beta-peptide 1-40 impair subsequent one-trial/day reward learning.

The injection of amyloid beta-peptide (Abeta) into rat CNS has been reported to induce cellular neuropathology. The present study investigated whether multiple intrahippocampal injections of Abeta 1-40 would impair one-trial/day reward learning 14 days later. Twenty-four male Sprague-Dawley rats, 3-4 months old, were injected with either Abeta 1-40 or distilled water into seven hippocampal sites bilaterally. Ten rats received 3 nmol Abeta 1-40 in 2 microl of distilled water per injection site, while 14 rats received distilled water alone. Following a 9-day recovery period, rats were gradually food deprived to 82% of their initial body weight. Fourteen days after the intrahippocampal injection, all rats received an initial training trial and three subsequent daily retention trials. Rats receiving Abeta 1-40 were significantly impaired on the second retention trial in terms of accuracy (number of unbaited alleys entered) and on the second and third retention trials in terms of speed (reciprocal of latency to reward). Histological analysis showed that Abeta 1-40 injections produced significant neuronal loss and gliosis. Abeta 1-40 immunoreactivity persisted locally at the injection site and in macrophages 2 weeks following the hippocampal injections. These effects appear to be sequence-specific; rats receiving Abeta 1-42 with a scrambled peptide sequence did not differ significantly from rats receiving distilled water alone in retention of the learning task or degree of histological damage.

Passive immunization against nicotine prevents nicotine alleviation of nicotine abstinence syndrome.

Passive immunization against nicotine interferes with its locomotor and pressor effects. The current study determined whether immunization could prevent another nicotine action: the reversal of nicotine abstinence syndrome. IgG containing 4.4-5.6% nicotine-specific antibody was isolated from rabbits immunized with 3'-amino-methyl-nicotine conjugated to a carrier protein. Twenty rats were rendered dependent by 7 days of subcutaneous infusion of 3.15 mg/kg/day nicotine (expressed as the base). Upon termination of nicotine infusion, each rat was injected intraperitoneally with 150 mg of IgG from normal serum (n=13) or from nicotine antiserum (n=7). Twenty-two and one-half hours later, all rats were observed over 15 min for baseline nicotine abstinence signs. Two and one-half hours after baseline observations, seven of the 13 rats pretreated with control IgG and all seven rats pretreated with nicotine-specific IgG were then challenged by 0.12 mg/kg (sc) nicotine. The remaining six rats pretreated with control IgG were challenged with saline alone. All rats were then observed again for abstinence signs. Nicotine injection caused significantly less reduction of abstinence signs in the immunized rats. The nicotine effect in immunized rats was comparable to the saline effect in nonimmunized rats. Immunization also significantly reduced free serum nicotine concentration and nicotine distribution to the brain. These results raise the possibility that immunization might prevent nicotine consumption from relieving the discomforts of smoking cessation.

Nicotine dependence: studies with a laboratory model.

Simple, rapid preclinical models of nicotine physical dependence and abstinence syndrome are needed to identify underlying neurobiological mechanisms and screen potential therapies. One such model induces dependence by 7 days of continuous subcutaneous nicotine infusion in the rat. Abstinence is initiated through termination of infusion or injection of nicotinic antagonist drugs. The result is an abstinence syndrome involving a pattern of behaviors somewhat resembling opiate abstinence in the rat as well as weight gain and depressed locomotor activity. The model has met a number of validity criteria and its essential features have been replicated in several laboratories. Several research groups have modified or extended the model by measuring emotional/motivational changes associated with nicotine abstinence such as conditioned aversion, intracranial self-stimulation (ICSS) thresholds and the startle response. Dependence models have been used to identify neurobiological systems that contribute to nicotine dependence, particularly endogenous opiate systems and the mesolimbic dopamine pathway. It is hypothesized that these different systems contribute to different behavioral aspects of nicotine abstinence syndrome. Increasingly used as a preclinical screening tool, the model has proved sensitive to various abstinence-alleviating therapeutic approaches, including some with already demonstrated clinical effectiveness.

Nociceptin/orphanin FQ (N/OFQ) induces a quasi-morphine abstinence syndrome in the rat.

Nociceptin/orphanin FQ (N/OFQ) is a neuropeptide that exerts antiopiate effects under some circumstances, and there is evidence that it contributes to opiate tolerance. This raises the question, might N/OFQ also contribute to opiate dependence and abstinence? Twenty-two male Sprague-Dawley rats were cannulated in the third ventricle and challenged 7 days later by third ventricle injection of 50, 200 or 1,000 ng N/OFQ or saline alone. Each rat was observed under "blind" conditions for 30 min beginning 15 min after onset of the third ventricle injection. There was a significant positive linear trend of signs as a function of N/OFQ dose. Subjects receiving saline had 18.0+/-2.0 (mean+/-SEM) overall abstinence-like signs, whereas subjects receiving 50, 200 or 1000 ng N/OFQ had 35.2+/-3.6, 49.8+/-2.6 and 63.5+/-9.7 signs, respectively. In 16 additional rats, abstinence-like signs induced by 1000 ng N/OFQ were significantly attenuated by low SC doses of morphine or clonidine. These results raise the possibility that N/OFQ might contribute to opiate dependence and subsequent abstinence syndrome. On the other hand, N/OFQ over a wide dose range induced abstinence signs with similar potency in morphine dependent and non-dependent rats.

A rodent model of cocaine abstinence syndrome.

This study introduces a rat model of cocaine abstinence syndrome based on quantitation of spontaneously emitted behaviors following termination of continuous drug exposure (analogous to established methods of assessing morphine and nicotine abstinence). Groups of eight male S-D rats were infused SC for 7 days via an osmotic minipump with saline alone or with 40 or 60 mg/kg/day cocaine HCl. Pumps were removed and rats were observed at 12, 24, 36, and 48 h postremoval. Each 15-min observation employed a checklist of abstinence signs including ptosis, chews, teeth chatters, gasps, writhes, seminal ejaculations, head shakes, and tremors. The high infusion rate group displayed significantly more signs than the low infusion rate group, which in turn, displayed significantly more signs than the saline group. Cocaine injection significantly reduced signs by 83.3%, while saline injection reduced them by only 4.9%. In another experiment, rats infused with 60 mg/kg/day showed significantly more signs 36 h postinfusion than before infusion, during infusion and 84 h postinfusion. Finally, 6.5 days of infusion resulted in significantly more abstinence signs than did 1.5 days of infusion. This rapid and simple model quantitated cocaine abstinence syndrome in a manner that was cocaine-reversible and related to the rate and duration of drug infusion.

A nicotine conjugate vaccine reduces nicotine distribution to brain and attenuates its behavioral and cardiovascular effects in rats.

Vaccination of animals to elicit drug-specific antibodies, or the passive transfer of such antibodies from other animals, can reduce the behavioral effects of drugs such as cocaine and heroin. To study the potential application of this approach to treating nicotine dependence, IgG was isolated from rabbits immunized with a nicotine-protein conjugate vaccine. Anesthetized rats received immune IgG containing nicotine-specific antibodies (Nic-IgG) or control-IgG i.v.. Thirty minutes later, rats received nicotine at 0.03 mg/kg i.v., equivalent on an mg/kg basis to the nicotine intake from two cigarettes by a smoker. Compared to control-IgG, Nic-IgG reduced the brain nicotine concentration in a dose-related manner (65% reduction at the highest IgG dose). Pretreatment with Nic-IgG also reduced the distribution to brain of five repeated doses of nicotine (equivalent to the nicotine intake from 10 cigarettes) administered over 80 min. To study blood pressure effects, rats received control-IgG or Nic-IgG 1 day prior to administering nicotine. Nicotine-induced systolic blood pressure increases were attenuated by Nic-IgG in a dose-related manner, and were almost completely blocked by the highest Nic-IgG dose. Pretreatment with Nic-IgG also completely prevented the nicotine-induced stimulation of locomotor activity observed in rats receiving control-IgG. Nic-IgG did not prevent locomotor activation from cocaine, demonstrating its specificity for nicotine. These data demonstrate that the administration of nicotine-specific antibodies can reduce or prevent some of the pharmacokinetic, cardiovascular, and behavioral consequences of nicotine in rats. Effects were observed at nicotine doses and nicotine serum concentrations equal to or exceeding those typically associated with nicotine exposure in cigarette smokers. A potential role for immunization in the treatment of nicotine dependence is suggested.

Nicotine abstinence syndrome precipitated by the competitive nicotinic antagonist dihydro-beta-erythroidine.

Rats infused subcutaneously with 9 mg/kg/day nicotine tartrate for 7 days exhibit behavioral abstinence signs following either termination of nicotine infusion or injection of the noncompetitive nicotinic antagonists mecamylamine (s.c.) or hexamethonium (ic.c.v.). This study examined the abstinence precipitating effects of dihydro-beta-erythroidine (DHbetaE), a competitive nicotinic antagonist. Twenty-four nicotine-dependent rats were injected in the third ventricle with 10, 18, or 25 microg DHbetaE in 20 microl saline or with saline alone and observed for abstinence signs over a 20-min period. There was a significant positive linear trend of overall abstinence signs as a function of dose, p < 0.01. In 12 nondependent rats, the high dose of DHbetaE did not induce more abstinence-like signs than saline alone. In a second experiment, 18 nicotine-dependent rats were injected s.c. with 1 or 6 mg/kg of the muscarinic antagonist scopolamine or with saline alone. Few abstinence signs were observed in any group: there was no significant drug effect. The results suggest that nicotine abstinence signs observed in the rat are specific to reduced stimulation of previously overstimulated nicotinic receptors.

The nitric oxide synthesis inhibitor nitro-L-arginine (L-NNA) attenuates nicotine abstinence syndrome in the rat.

Nitric oxide synthesis contributes to opiate tolerance and dependence. Nicotine dependence and abstinence syndrome in the rat appear to involve opiate mechanisms. Therefore, it was postulated that nitric oxide synthase (NOS) activity might be essential for the expression of nicotine abstinence syndrome. Twenty-one rats were rendered dependent by SC infusion of 9 mg/kg per day nicotine tartrate via Alzet osmotic minipump. Rats were pretreated SC with vehicle alone, or with 18 or 30 mg/kg of the NOS inhibitor L-NNA (nitro-L-arginine). Thirty minutes later, rats were challenged by 1 mg/kg of the nicotinic antagonist mecamylamine SC and observed for 30 additional minutes. Rats pretreated with vehicle displayed a total of 68.7+/-8.0 mecamylamine-precipitated abstinence signs (mean+/-SEM), while those receiving 18 or 30 mg/kg L-NNA had 12.7+/-2.0 and 5.1+/-1.7 signs, respectively. All three groups differed significantly from one another according to Dunn's post-hoc procedure. Rats pretreated with L-NNA combined with an excess of the NOS substrate L-arginine had significantly more mecamylamine-precipitated abstinence signs than rats receiving L-NNA combined with D-arginine. Also, D-NNA, which does not selectively bind to NOS, was significantly less effective than L-NNA in preventing mecamylamine-precipitated abstinence syndrome. Additional studies determined the effect of L-NNA on spontaneous nicotine abstinence syndrome. Rats were assessed for abstinence signs at 17 and 20 h after termination of nicotine infusion. They received injections of 9, 18, or 30 mg/kg L-NNA SC or vehicle alone immediately before the 20-h observation; all rats were observed for 30 min. Signs at 20 h (post-injection) as a percentage of signs at 17 h (pre-injection) declined significantly as a function of L-NNA dose. Once again, this effect was attenuated significantly more by co-administration of L-arginine than by D-arginine. The overall pattern of results suggests that nitric oxide synthesis is critical to the expression of nicotine abstinence syndrome.