Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
the success of root canal therapy is dependent on understanding the anatomy of root and root canal morphology.1,2 awareness and understanding of the presence of unusual external and internal root canal morphology largely contributes to the successful outcome of the root canal treatment . in literature ,
description of the mandibular first premolar is typically of a single - rooted tooth.3,4 two - rooted , three - rooted , and four - rooted varieties have also been reported , but are rare.5,6 the root frequently has developmental depressions or grooves on both the mesial and distal surfaces . according to slowey , the mandibular premolars may present the greater difficulty of all teeth for a successful endodontic treatment.7 a study at the university of washington in 1955 assessed the failure rate of non - surgical root canal therapy ( nsrct ) in all teeth .
numerous endodontic failures after a routine treatment and flare - ups during the course of nsrct are cited as evidence
. it could be because of variations in root canal morphology and difficult access to additional canal systems.8 this case report presents a successful , non - surgical management of mandibular left second premolar with three roots and root canals and a first premolar with two roots using a cone beam computed tomography ( cbct ) .
a 31-year - old male patient was reported to the department of conservative dentistry and endodontics , mnr dental college and hospital with a chief complaint of pain and pus discharge in the lower left back tooth region since 3 months .
, there was a gingival inflammation with recession in relation to tooth numbers 34 , 35 , 36 .
electric pulp testing and thermal testing of the teeth indicated non vitality of 34 , 35 , and 36 . a confirmatory diagnosis of acute apical abscess in relation to 34 , 35 , and 36 was established and endodontic therapy was planned .
the mesiodistal width of the crown is lesser than mesiodistal diameter of the root and for further confirmation a cbct ( gentex ) , was planned .
cbct with a 3d reconstruction confirmed a three rooted 34 and two rooted 35 ( figure 1b - d ) .
( a ) pre - operative radiograph showing first and second premolar and first molar .
the area was anaesthetized using 2% lignocaine with 1:80,000 adrenaline ( lignox ) and isolated with a rubber dam .
an access cavity was prepared with a modification that it had a cut at the buccoproximal angle from the entrance of the buccal canals to the cavosurface angle , so that it is results in a t - shaped outline ( figure 2a ) .
a working length was determined with an apex locator ( root - zx ) ( figure 2b ) . with crown down technique , cleaning and shaping
were performed with twisted file and protaper rotary instruments ( dentsply mailfilter ) . abundant irrigation with 3% sodium hypochlorite solution is done .
biomechanical preparation is done up to f2 . before obturation irrigation with 17% , edta and saline are done .
obturation is done with gutta - percha and resin sealer ( ah plus , dentsply ) by cold lateral condensation ( figure 2c ) .
the coronal access was restored with resin composite ( 3 m espe ) ( figure 2d ) .
successful and predictable endodontic treatment requires knowledge of biology , root canal anatomy , and careful radiographic evaluation in order to determine number of roots and root canals .
preoperative parallel radiographs , as well as mesial or distal angled radiographs , can help to determine number of roots .
the diagnosis and management of extra roots or root canals in mandibular premolars pose an endodontic challenge .
failing to locate and obturating a root canal is the major cause of failure in endodontic therapy .
hoen and pink found 42% incidence of missed roots or canals in the teeth that needed retreatment.9 according to cleghorn , the incidence of three rooted mandibular first premolars is 0.2%.10 hence , it is import that all the canals be located and treated during the course of nonsurgical endodontic therapy .
rodig and hulsmann have reported a case of mandibular second premolar with three separate roots and root canals diagnosed using intraoral periapical radiographs.2 wong and al - fouzan have published cases of mandibular second premolars with four canals.11,12 tzanetakis et al .
have reported endodontic management of mandibular second premolar with four root canals diagnosed with the aid of operating microscope.13 it has been established that a root with a tapering canal and a single foramen is the exception rather than the rule .
serman and hasselgren ( 1992 ) reported a high incidence of multiple roots ( 18.1% ) and root canals in mandibular premolar teeth in a series of radiographic surveys with mandibular first premolars involved in 15.7% of patients and mandibular second premolars in 7% of patients.14 studies by lu et al .
are similar to slowey suggestions that mandibular premolars are the most difficult to treat endodontically and also the apical configuration of these teeth was found to be complex.15 thus , a careful understanding and diagnosis of canal anatomy is of utmost importance for successful management of such cases .
accurate preoperative radiographs of good quality along with an occlusal view , into the access opening and down the chamber of a mandibular premolar tooth , rarely shows any chamber floor , even when a suspected bifurcation of the canal is seen on the radiograph .
the surgical operating microscope sometimes aids in canal visualization of a canal system branching off the main canal . a fine , curved stainless steel file with a good tactile sense is the best guide to the detection of the accessory canals.16 a modification in the access cavity preparation is often needed for unhiding the additional orifices of the root canals or the orifices of the extra roots for a better instrumentation . when present the roots are usually  mesiobuccal , distobuccal , and a lingual root .
at least two radiographs , with the second radiograph angulated from 15 to 20 either mesial or distal from the horizontal long axis of the root , are required to reliably diagnose more than one root or root canal system in premolar teeth .
a sudden narrowing of the main canal on a parallel radiograph was a good criterion to judge root canal multiplicity.17 however , martinez - lozano et al .
recommend up to 40 mesial angulation from horizontal as more reliable in identifying the extra canals.18 deviation of the x - ray angle from the vertical axis of 15 to 30 was effective only in the mandibular first premolar in helping to visualize canal anatomy of premolar teeth .
dyes , fiber - optic transillumination , magnifying loupes , and sodium hypochlorite bubbling in the extra canals help in locating additional canals . with the advent of advanced imaging techniques , an understanding of complex anatomies
cbct is better of digital radiographic techniques in identifying multiple root canal systems in the mandibular incisor , mandibular first premolar , and maxillary first molar teeth.19
management of teeth with morphological variations presents a challenge , which requires proper instruments and the knowledge to use the instruments effectively .
advanced imaging techniques like cbct are valuable tools in diagnosing and managing cases , which deviate from the regular pattern .
the present case report emphasizes the need to understand , interpret , and manage a three rooted mandibular first premolar with three roots which has been successfully managed using cbct .

Answer:
understanding the morphological anatomy of the root and root canal systems of the teeth increases the success rate of endodontic therapy .
 advanced diagnostic imaging techniques like cone beam computed tomography ( cbct ) are an essential aid in understanding the anatomy of teeth especially in mandibular premolars .
 most commonly mandibular first and second premolars have a single root and a single canal .
 however , multiple root and canals have also been reported .
 the present case report discusses endodontic management of a three rooted mandibular first premolar using cbct .


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
Multiple hydride reduction pathways in isoflavonoids

Paper sections:
Background

The reduction of isoflavones 1 has been actively studied during the last twenty years, owing to the range of interesting biological effects [1][2][3] -estrogenic activity, promise in cancer, osteoporosis, and coronary heart disease prevention -shown by the isoflavones themselves and their reduced metabolites. There are some reports [4][5][6][7][8] of total syntheses of reduced isoflavonoid structures from commercially available starting materials but overall yields in these multistep procedures tend to be low, and free hydroxy groups are not compatible. Another strategy involves the hydrogenation of isoflavones using a palladium or platinum catalyst but mixtures of reduction products are often formed [9,10]. Certain hydride reagents have been tested, as discussed below, for the reduction of simple or protected isoflavones but many of the early results are contradictory or rely on indeterminate product characterization.

The reduction of simple (nonflavonoid) β-alkoxy-α,β-unsaturated ketones by hydride reagents (NaBH 4 , LiAlH 4 , DIBAH) occurs normally by 1,2-attack, this being a key step in the well known "carbonyl transposition" of 1,3-diketone enol ethers into enones (R 3 O-CR=CR 1 -COR 2 → R-CO-CR 1 =CHR 2 ). [11][12][13][14][15] Prior to our work there were no reports on the reduction of isoflavones containing free hydroxy groups which nevertheless are common, usually at one or several of the C-5, C-7 and C-4' sites, in the naturally occurring isoflavonoids. It is to be expected that the presence of the phenolic hydroxyls, or the derived phenolate anions, will alter the reactivity pattern of the parent isoflavone system, besides perhaps decreasing the overall reactivity due to solubility reasons. For example, any tendency of hydride attack at the C-2 will be opposed by electron feeding from the 4'-OH group while an OH group at C-5 or C-7 will discourage attack at C-2 and C-4. Thus there was ample room for the development of reliable methods for the synthesis of hydroxy-substituted isoflavone metabolites, and for clarification of the course of reduction of isoflavones with various hydride reducing agents. We present here experimental details of our own results in this field together with a thorough survey of the literature. The discussion is based on the types of reduced isoflavonoid structures formed (Figure 1), i.e., isoflavanones 2, cis-isoflavan-4-ols 3, trans-isoflavan-4-ols 4, the ring opened α-methyldeoxybenzoins 5 and 1,2-diaryl-2-propen-1-ols 6, and isoflavenes 7 and 8 (hydride reductions do not lead to isoflavans 9, which however are obtained by catalytic hydrogenation [10,16,20]). Incidentally, it is appropriate to point out that flavones do not undergo similar reductive metabolism in mammals as described above for isoflavones. We will nevertheless present at a later date certain findings on the hydride reduction pathways in flavones.

Results and Discussion

Isoflavanones (2) Isoflavanones result from the 1,4-reduction of isoflavones. The resonance contributor 10 will encourage this mode of attack. DIBAH, normally a preferential 1,2-reducer, reacts with methoxy-, benzyloxy-, MOMO-and MEMO-substituted isoflavones to give the isoflavanones in 40-93% yield [16,[21][22][23] (Table 1). Our own work has shown that even unprotected hydroxy-substituted isoflavones are reduced by a large excess of DIBAH in 50-70% yield (Table 1). The simple borohydride reagents reduce isoflavones to the isoflavanols (see below) but the Selectrides ® give 60-88% yields of isoflavanones in the absence of hydroxy substituents according to our results (Table 1). There is no significant difference between the K-and L-Selectride ® . In the literature, there is an isolated report of the reduction of a MOM substituted isoflavone by L-Selectride ® in 40% yield (Table 2) [16]. Methoxy substituted isoflavones have also been reduced by sodium hydrogen telluride to give isoflavan-4-ones in 61-71% yields [24].    trans-isoflavan-4-ols 4 (Table 3). [16,29,34] Isoflavanones are reduced by electrophilic hydrides (borane-tetrahydrofuran, bistert-butylthioethane borane) diastereoselectively to cisisoflavan-4-ols, but a large excess of the reducing agent is usually needed [29].

Although it was realized by the early workers that diastereomeric mixtures of isoflavanols would presumably be formed, there were no reliable methods to determine their structures. In some papers, the products are summarily assigned the cis [25,26] or trans [35][36][37][38] structures. However, rigorous NMR analysis has recently made it possible to establish cisand trans-structures for the isoflavanol products and to study their conformational equilibria [32,34]. Borohydride reductions generally give a small preference for the cis products as suggested by Cram's rule [39]. We are not aware of any examples in the literature of single enantiomers of isoflavanone or isoflavanol metabolites, nor have such compounds been reported as hydride reduction products of isoflavones. In view of the significant biological properties of the reduced metabolites it will be interesting to examine the behaviour of the pure enantiomers.

2-Isoflaven-4-ols (11)

There are very few reports of this class of compounds, either from reductive processes or otherwise. In 1965, the reduction of the parent isoflavone by NaBH 4 in EtOH or diborane in THF was claimed [28] to furnish 2-isoflaven-4-ol in 75-76% yield, but unfortunately the characterization of this product relied on elemental analysis only. More recently, Japanese workers [40] reported that the reduction of 12 (Figure 2) by NaBH 4 in the presence of PdCl 2 in THF-H 2 O gave a 1:1 mixture of the ketone 13a and the diol 13b (Figure 2). A 1 H NMR spectrum was given for the latter isoflavenol but there appear to be certain discrepancies, notably in the δ value (8.69) reported for the H-8 which is some 2 δ units in excess of what would be expected for such a vinyl ether proton. Thus more work is required to fully confirm the nature of this class of reduction products. In the event, in our studies the reduction of isoflavone 1a by NaBH 4 in the presence of PdCl 2 in THF-H 2 O gave a 82:18 mixture of cisand trans-isoflavan-4-ol 3a, 4a while no 2-isoflaven-4-ols were observed. The absence of such 1,2-reduction products, or structures conceivably derivable thereof such as 2-or 3-isoflavenes (7,8), even in the CeCl 3 -complexed NaBH 4 reductions, must reflect the good stabilization obtainable via resonance heteroring stabilization (10) in the isoflavones. As already mentioned, this is in contrast to the behaviour of simple nonflavonoid β-alkoxy-α,β-unsaturated ketones which prefer 1,2attack by hydride.

Isoflavenes (7,8) and isoflavans (9) In the early work, [41] there is a mention of 7,4'-dimethoxy-2methyl-3-isoflavene being obtained in 15% yield from the reduction of the corresponding isoflavone by LiAlH 4 in Et 2 Obenzene but there is no structural data on the product other than elemental analysis, itself quite accurate. Similarly 2',4'dimethoxy-3',6,7-trihydroxyisoflav-3-ene was reported from the reduction of 2',4'-dimethoxy-3',6,7-trihydroxyisoflavan-4-one with LiAlH 4 in low yield [42]. More recent work by us [43] and others [16,44] would indicate that the normal course of LiAlH 4 reduction of isoflavones leads to deoxybenzoins and propenols (see below and Table 4).

Published syntheses of 2-and 3-isoflavenes involve the reduction of 3-arylcoumarins, [45][46][47] the corresponding aldehyde hemiacetals, [7] isoflavylium salts [48][49][50] or of isoflavones by the Clemmensen reaction [51]. Low-yielding non-reductive routes to 2-and/or 3-isoflavenes have also been reported [52,53]. 2-Isoflavenes 7 however remain mostly poorly character-ized, and some of the NMR spectral details reported [7,51,52] appear inconsistent with the 2-isoflavenoid structure. As far as the NMR spectra of 2-isoflavenes are concerned, a recent study clears this issue by 2D NMR work on a natural 2-isoflavene, [54] establishing that the H-2 and H-4 protons appear at δ 6.87 and 3.61, respectively, much as expected by correlation data shift calculations. Isoflavans (9) have not been prepared by hydride reductions, but by catalytic hydrogenation of isoflavones [10,[16][17][18][19][20].

Deoxybenzoins ( 5) and propenols (6) Isoflavanones undergo a facile retro-Michael-type ring opening [21,55] under basic conditions to give the propenone intermediate 14 (Figure 2), sometimes considered [56] to be an independent isoflavone metabolite but presumably just an artefact in reality. As regards the synthesis of isoflavanones by DIBAH reduction of isoflavones (see above), we found that unless the workup is done with cold methanolic HCl, some amount of the propenone 14 will be formed and reduced further to the deoxy-benzoin 5. If on the other hand the deoxybenzoins are the actual synthetic targets, the reducing agent of choice is LiAlH 4 in THF. This works very well for isoflavones bearing a hydroxy group at C-7 such as genistein, but in isoflavones lacking a 7-OH group another reaction pathway competes leading to the propenols 6 [43] as byproducts (see below). We have discussed a possible mechanism to explain these hydroxyl-dependent divergent pathways [43].

To summarize, all hydride addition reactions with isoflavones appear to involve an initial 1,4-addition to give the isoflavanone enolate. In a hydroxylic solvent, or even on workup under basic conditions, the ketone is generated, and reduced further to the saturated alcohol (NaBH 4 ). In a nonprotic solvent, the β-aryloxyenolate will undergo a retro-Michael addition, giving the phenolate anion of the ring opened 2-propen- The dietary isoflavonoids are mainly metabolized in man via reductive pathways, leading to the reduced structural types discussed above (Figure 3). These compounds are often more estrogenic than the starting isoflavones. Research interest in many fields including medicine, nutrition and biosynthesis and metabolism thus converge on the reduced isoflavonoids. The work described in this paper shows that most structural types of reduced isoflavonoids are now reliably available in satisfactory or good yields by hydride reductions. Although not discussed here, it is clear that D atoms may be introduced in the same way which is very useful in the quantitation of the naturally occurring compounds by GC-MS selected ion monitoring techniques [61].

Supporting Information

Supporting Information File 1

Experimental details and characterisation data.

[http://www.beilstein-journals.org/bjoc/content/ supplementary/1860-5397-2-16-S1.doc]

Answer: BackgroundIsoflavonoids are of interest owing to their appearance in metabolic pathways of isoflavones, and their estrogenic and other physiological properties, making them promising lead compounds for drug design. ResultsThe reduction of isoflavones by various hydride reagents occurs by a 1,4-pathway in contrast to ordinary β-alkoxy-α,β-unsaturated ketones. Isoflavan-4-ones, cisand trans-isoflavan-4-ols, α-methyldeoxybenzoins or 1,2-diphenylprop-2-en-1-ols are obtained depending on the hydride reagent, mostly in good yields. The stereoselective reduction of isoflavan-4-ones is also discussed. ConclusionThe work described in this paper shows that most structural types of reduced isoflavonoids are now reliably available in satisfactory or good yields by hydride reductions to be used as authentic reference compounds in analytical and biological studies.


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
musicians often experience musculoskeletal pain as a result of lengthy and long - term
 instrument performance .
more students enrolled in music schools note upper limb pain
 compared with students enrolled in ordinary schools1 .
it has also been reported that the incidence of upper limb pain is
 higher in those who have longer practice times .
therefore , it can be said that upper limb
 pain in musicians is a symptom of overuse , with lengthy and long - term instrument performance
 being contributing factors .
musculoskeletal pain in musicians is common not only in the
 upper limbs but also in the lumbar and cervical regions , as well as in the shoulder
 girdle2 .
for example , it is conceivable that when playing a heavy instrument
 such as the tuba , a large load is applied to the trunk to maintain the performance posture .

furthermore , as instruments in a marching band are played while marching , a large load is
 probably also applied to the lower limbs .
however , the performance postures
 of various types of instruments have not been sufficiently investigated .
thus , the present
 study clarified the characteristics of the standing performance posture for the trumpet and
 the marching euphonium and investigated the effect of the performance postures of these
 instruments on the lower limb musculoskeletal system .
the subjects were 10 female university students in japan . their ( mean  sd ) age was 20.5
 1.3  years , their height was 159.6  6.2  cm , and their weight was 55.1  7.2  kg .
because the subjects were not
 professional trumpet or marching euphonium performers , they all received sufficient
 instruction from the instructor regarding the trumpet and marching euphonium performance
 posture prior to measurements .
the purpose and contents of the study were sufficiently
 explained to the subjects , whose consent to participate in the study was obtained .

additionally , approval was obtained from the shijonawate gakuen university ethics committee
 ( approval number 23 - 2 ) .
the subjects adopted a closed - leg resting standing position , a trumpet performance posture ,
 and a marching euphonium performance posture .
all instrumental performance postures were
 adopted in the standing , and the subjects focused directly ahead on a mark positioned at eye
 level . subjects maintained performance posture without actually playing the instrument .
the
 angle and muscle activity of the trunk and lower limbs were measured while the postures were
 maintained .
the measurement was performed in the sequence of the resting standing position ,
 the trumpet performance posture , and the marching euphonium performance posture .
the trunk
 and lower limb angles were measured using a three - dimensional motion analysis device
 ( cms - hs , zebris medical gmbh , isny , germany ) .
markers were attached to the lateral
 malleolus , lateral epicondyle of the femur , greater trochanter , and acromion on the left
 side of the subjects .
the sampling frequency was 100  hz , and the measurement time was 10 s.
 measurements were performed as soon as the subjects could maintain a stable performance
 posture .
the collected data were processed by image analysis software ( win - date , zebris
 medical gmbh ) , and the angles of knee flexion , hip flexion , and anterior tilt of the trunk
 were calculated .
the angle of knee flexion was considered as the angle formed between the
 line linking the lateral malleolus and the lateral epicondyle of the femur and the line
 linking the lateral epicondyle of the femur and the greater trochanter .
the angle of hip
 flexion was considered as the angle formed between the line linking the lateral epicondyle
 of the femur and the greater trochanter and a vertical line .
the anterior tilt angle of the
 trunk was considered as the angle formed between the line linking the acromion and the
 greater trochanter and a vertical line . a surface myograph ( myosystem 1200 , noraxon inc . ,

the muscle activities measured
 were those of the cervical paraspinal muscles , upper fibers of the trapezius , lumbar
 paraspinal muscles , gluteus maximus , rectus femoris , biceps femoris , and lateral head of the
 gastrocnemius on the left side .
after treating the skin sufficiently to create a skin
 resistance of no greater than 10  , electrodes ( blue sensor p-00-s , ambu a / s , ballerup ,
 denmark ) were attached parallel to the muscle fibers at the center of each muscle .
spacing between the electrodes was 25  mm , the
 sampling frequency was 1,000  hz , and the sampling time was 10 s. measurements were performed
 as soon as subjects could maintain a stable performance posture .
the collected data were
 subjected to full - wave rectification using electromyogram analysis software ( myoresearch ,
 noraxon inc . ) , and the average amplitude of the central three seconds was determined .
the
 average amplitude of each muscle was normalized as 100% according to the average amplitude
 of the 3-s maximum voluntary contraction .
statistical analysis entailed a one - way analysis of variance and multiple comparison using
 tukey 's method .
mean  sd . a : significant difference between the standing position and the trumpet
 performance posture ( p<0.01 ) .
b : significant difference between the standing position
 and the marching euphonium performance posture ( p<0.01 ) .
c : significant difference
 between the trumpet performance posture and the marching euphonium performance posture
 ( p<0.05 ) mean  sd .
a : significant difference between the standing position and the marching
 euphonium performance posture ( p<0.01 ) .
b : significant difference between the
 standing position and the marching euphonium performance posture ( p<0.05 ) .
c :
 significant difference between the trumpet performance posture and the marching
 euphonium performance posture ( p<0.01 ) the anterior tilt angle of the trunk decreased significantly in the trumpet and marching
 euphonium performance postures compared with the resting standing position , as well as in
 the marching euphonium performance posture compared with the trumpet performance posture
 ( table 1 ) .
the muscle activity of the cervical
 paraspinal muscles , upper fibers of the trapezius , and lumbar paraspinal muscles increased
 significantly in the marching euphonium performance posture compared with the resting
 standing position , as well as in the marching euphonium performance posture compared with
 the trumpet performance posture ( table 2 ) .

however , there were no significant differences in other measurement items between the
 postures .
the anterior tilt angle of the trunk can be rephrased as an increase in the posterior tilt
 angle of the trunk .
this is likely a means for maintaining the combined center of gravity of the
 instrument and the body in the most stable position possible .
an increase in the posterior
 tilt angle of the trunk increases the lumbar lordosis angle .
this increase results in
 tension being applied to the anterior tissues of the lumbar spine , such as the anterior
 longitudinal ligament , and compressive force being applied to the zygapophyseal joints4 .
christie et al . reported that an increase
 in the lumbar lordosis angle while standing is associated with chronic low back pain5 .
consequently , maintaining the performance
 posture for the trumpet and the marching euphonium for a long period can contribute to low
 back pain .
no significant difference was found in the muscle activities of the lumbar paraspinal
 muscles between the resting standing position and the trumpet performance posture , but a
 significant increase was noted in the marching euphonium performance posture compared with
 the resting standing position .
the lumbar paraspinal muscles are antigravity muscles which
 are contracted continuously while standing , thus easily incurring mechanical stress .
it is
 conceivable that , since the muscle activity of the lumbar paraspinal muscles increases
 during the marching euphonium performance posture , holding the performance posture for a
 long time increases the load on the lumbar paraspinal muscles and is therefore a factor
 leading to lumbar fatigue and low back pain .
the muscle activity of the upper fibers of the
 trapezius increases in line with instrument weight in the trumpet to marching euphonium
 postures .
when holding these instruments , the shoulder joint flexes and abducts , while the
 scapula rotates up and elevates .
the muscle activity of the upper fibers of the trapezius is
 likely to increase to maintain such a posture .
we also found that muscle activity of the
 cervical paraspinal muscles increased significantly in the euphonium performance posture
 compared with the resting standing position . since the posterior tilt angle of the trunk
 increases in the marching euphonium performance posture , it is necessary to tuck in the chin
 to face forward
chin - in posture  and is
 considered a posture in which the muscle activity in the cervical area including the
 cervical paraspinal muscles increases6 .
 sustained contraction of these muscles is a likely factor of muscle fatigue .
furthermore ,
 obstruction of blood flow by sustained muscle contraction will result in myalgia7 .
therefore , holding the trumpet and marching
 euphonium performance postures for a long time would be factors of myalgia .
the present findings suggest that the trumpet and marching euphonium performance postures
 increase the load on the cervical and trunk musculoskeletal system .
moreover , the load on
 the musculoskeletal system increases in line with increased instrument weight .
however , the
 trumpet and marching euphonium performance postures do not affect the musculoskeletal system
 of the lower limbs .
therefore , we consider it important to evaluate the cervical and trunk
 musculoskeletal systems and to conduct conditioning coaching appropriate for trumpet and
 marching euphonium performers .
because these instruments are supported by the left hand and
 played with the right hand , the trunk and lower limb musculoskeletal system on the left
 side , that is , the supporting side , was measured in the present study .
we plan to measure
 the trunk and lower limb musculoskeletal system on the right side to elucidate the effect of
 performance postures on the whole body .
in addition , it is possible that the trunk and lower
 limb musculoskeletal system is affected differently by the technique used to hold the
 instrument with the left hand during trumpet and the marching euphonium performance . because
 the angles and muscle activities of the upper arm were not measured in the present study , we
 plan to perform these measurements in a future study to elucidate the influence of different
 instrument holding techniques on the trunk and lower limb musculoskeletal systems .

Answer:
[ purpose ] the purpose of the present study was to investigate the effect of trumpet and
 marching euphonium performance posture on the trunk and lower limb musculoskeletal system .

 [ subjects ] the subjects were 10 female university students . [ methods ] subjects maintained
 a resting position , a trumpet performance posture , and a marching euphonium performance
 posture . the angles and muscle activities of the trunk and
 lower limbs were then measured .

 [ results ] the anterior tilt angle of the trunk decreased significantly in the trumpet and
 marching euphonium performance postures compared with the resting standing position , as
 well as in the marching euphonium performance posture compared with the trumpet
 performance posture .
 the muscle activity of the cervical paraspinal muscles , upper fibers
 of the trapezius , and lumbar paraspinal muscles increased significantly in the marching
 euphonium performance posture compared with the resting standing position , as well as in
 the marching euphonium performance posture compared with the trumpet performance posture .

 [ conclusion ] the results suggest that the performance position for trumpet and the
 marching euphonium performance increases the load on the cervical and thoracic
 musculoskeletal system , which increases with greater instrument weight .
 however , the same
 instrument performance postures had no affect on the musculoskeletal system of the lower
 limbs .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
risperidone has been reported to be effective in management of disruptive behaviors , including hyperactivity , irritability , aggression , and temper tantrums . increased appetite , weight gain , headache , and sedation
literature search revealed only four published reports of risperidone - related bleeding , including hemorrhagic cystitis,1 ) nasal bleeding,2,3 ) and gastrointestinal bleeding.4 ) we hereby describe the first pediatric case of gingival bleeding during risperidone treatment .
an 11-year - old - girl was referred to our out - patient clinic for her hyperactivity , temper tantrums , sleep problems , and self - injurious behaviors . according to her psychiatric assessment and psychometric evaluation ,
she was started on risperidone 0.25 mg / day treatment for her disruptive behaviors and two weeks later the dose was increased to 0.5 mg / day .
one - week after the dose increase , she experienced gingival bleeding when she brushed her teeth .
risperidone was considered to be the reason for bleeding , therefore we decided to reduce the dose to 0.25 mg / day .
gingival bleeding ceased within a week . because worsening of her behavioral problems , her mother increased the dose to 0.33 mg / day .
she experienced gingival bleeding rarely ( twice a month ) and mildly during this dose regime , therefore we stopped the medication .
we decided to change risperidone to methylphenidate ; however , her parents refused to continue to the treatment because of their worries about the potential side effects .
she had no history of any bleeding disorder or any other medical condition including current allergies .
she was not taking any other medication other than risperidone at the time of the development of bleeding .
there are several case reports about risperidone - related bleeding ; however , to our knowledge , there is no report of gingival bleeding associated with risperidone in the literature .
we presented a case who experienced gingival bleeding when risperidone dose was increased to 0.5 mg / day , and subsided after decreasing the dose to 0.25 mg / day , suggesting a dose - dependent side - effect .
however , the chronological relationship between the time of risperidone 0.5 mg / day administration and emergence of bleeding in the absence of an identifiable medical condition suggests risperidone to be the causative agent .
there was no other agent likely to be the cause of bleeding , except risperidone , and bleeding ceased when the dose was decreased .
although an etiological relationship between risperidone use and gingival bleeding can not be drawn from a single case , the naranjo probability scale score ( 8) reveals a probable relationship.5 ) the bleeding side effect of risperidone might be caused by several mechanisms , including thrombocytopenia and 5-hydroxytryptamine 2a ( 5-ht2a ) receptor antagonism.3 ) thrombocytopenia is a known adverse effect of atypical antipsychotics and has also been reported during risperidone.6 ) in our reported case platelet count was normal , therefore , gingival bleeding could not be a consequence of thrombocytopenia .
antagonism of 5-ht2a receptor was suggested to cause bleeding by inhibiting the release of vasoconstrictors from platelets and reducing the platelet aggregation.4 ) therefore , we may speculate that risperidone s high affinity to 5-ht2a receptors might have probably resulted gingival bleeding .
this case suggests that bleeding associated with risperidone may be a dose - dependent side effect .
however , these potential explanations may not describe the entire mechanism of this adverse reaction .
it is also possible that she might have some undetermined predisposing factors for bleeding that is triggered by risperidone .
there are several reports on gingival bleeding during anti - depressants;7 ) however , this is the first case on gingival bleeding associated with risperidone . although bleeding is a rare side effect , clinicians should be aware that risperidone may cause bleeding .
risperidone may also increase the risk of bleeding in susceptible patients with a history of coagulation disorders , and with concomitant use of other drugs , including non - steroidal anti - inflammatory drugs , aspirin , or other medications that affect coagulation .

Answer:
there are several case reports on risperidone - related bleeding ; however , to our knowledge , there is no report about gingival bleeding associated with risperidone in the literature .
 we presented a case who experienced gingival bleeding when risperidone dose was increased to 0.5 mg / day , and subsided after decreasing the dose to 0.25 mg / day , suggesting a dose - dependent side - effect .
 the bleeding side effect of risperidone might be caused by several mechanisms , including 5-hydroxytryptamine 2a receptor antagonism .
 although bleeding associated with risperidone is rarely reported , clinicians should be aware of this side effect .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
sensitive skin syndrome is a common and challenging condition , yet little is known about its underlying pathophysiology .
sensitive skin is a common term used by patients and clinicians , as well as the cosmetic industry , and represents a complex clinical challenge faced by dermatologists and other skin care professionals .
patients with sensitive skin often present with subjective complaints that are out of proportion to the objective clinical findings .
the patients complain of severe facial irritation , burning , and/or stinging after application of cosmetic products and toiletries such as sunscreens and soaps , yet they do not demonstrate the clinical stigmata of scaling , induration , and/or erythema that would be expected in known inflammatory or allergic processes .
the condition is often worsened by specific climatic conditions and may affect areas other than the face .
maibach described the cosmetic intolerance syndrome ( cis ) , which probably covers the bulk of the clinical presentation of the sensitive skin syndrome ( sss ) .
fisher is credited with coining the term status cosmeticus to describe one extreme of the natural history of the cis in which the patient gradually becomes completely intolerant to the application of any cosmetic product .
fundamentally , sss is a state of hyperreactivity to environmental stimuli , presenting with a clear clinical picture and resulting from a single underlying pathology or a combination of pathologies .
defined as a self - diagnosed condition , sss is by definition difficult to quantify .
some of the contradictions between investigators could be explained by flawed methodologies since the scientific community has yet to identify an acceptable objective screening test for sensitive skin .
however , it is not only the subjective nature of the complaints that make sss difficult to diagnose .
robinson , by performing patch testing with sodium dodecyl sulfate ( sds ) and looking for intra - individual response patterns , found that there is significant positive correlation between sds and other irritants but noted overall low correlation coefficients .
he therefore deduced that it is inappropriate to define a subject 's reaction to a chemical based on his or her response to another irritant .
she skin - tested 58 subjects with history of strong positive sds or lactic acid response .
sds- or lactic acid - positive group , a reaction to one irritant could not predict a reaction with another . to further complicate matters
there is evidence to suggest that no correlation exists between the lactic acid stinging test and the response to sds .
this data resonate the idea that even the reference irritants commonly used in studies of this topic do not correlate with each other and with hyperreactivity tendencies .
finally , judge tested 22 nonatopic adults with varying doses of sds and found marked inter - individual variation in the response threshold .
this complexityreinforces the need for a thorough diagnostic algorithm and , specifically , the need to test patients with multiple , repeated and complete ( i.e. all cosmetics applied by the patient at home ) patch testing before making a diagnosis .
in order to formulate a systematic clinical approach , the medical and cosmetic communities have attempted to characterize the condition .
lacking an objective screening test , investigators resorted to epidemiological studies using patient surveys . in a large epidemiological study in the uk (
n = 2316 ) , a staggering 51.4% of women and 38.2% of men self - reported themselves as having sensitive skin . of note ,
interestingly , atopy did not appear to predict self - perceived sensitivity in the participating women .
in addition , in the same study self - reports of sss symptoms were statistically over - represented in the  self - reported sensitive cohort compared to the  self - reported nonsensitive cohort .
this finding validates the link between self - perception of sensitive skin and neurosensory discomfort .
two recent studies in the us and europe made similar observations . in the us ,
females were significantly more concerned about sensitive skin than men ; however , no age or ethnic differences were found .
the european study reported an overall sensitive skin prevalence of 38.4% and found no ethnic differences .
the european study , once again , demonstrated that people who reported having sensitive skin were significantly more likely to experience sss symptoms . of note ,
both the american and european studies used large samples ( n = 994 and n = 4506 , respectively ) ; however , they were both limited by a phone survey methodology and the lack of any objective assessment . in light of the increased incidence of self - reported hypersensitivity in females ,
he compared the patch test responses of 384 patients to sds as the positive control and found increased reactivity in males compared to females .
lammintausta tested seven males and seven females with sodium lauryl sulfate ( sls ) and then performed visual inspections , transepidermal water loss measurements , and dielectric water content measurements but like other investigators found no reactivity differences between males and females , adding to the overall controversy .
female self - perception of sensitivity is consistently increased compared to that of males , yet when put through objective reactivity testing the trend is unclear .
ethnic differences in skin reactivity have been explored through the years , leading to the clinical hypothesis that black skin is less reactive than caucasian skin , which is in turn less reactive than asian skin . however , an epidemiological telephone survey performed in the us ( n = 811 ) revealed similar incidence of self - reported sensitive skin across four major ethnic groups ( afro - americans , asians , euro- american , and hispanics ) . the incidence rate of 52% is comparable to the incidence found in the uk ( see above ) .
the investigators did , however , find minimally statistically significant ethnic differences in the self - reported triggers and symptoms of sensitivity : afro - americans reacted less to environmental and alcoholic triggers ; hispanics reacted less to alcohol ; asians reacted more to wind , spices , and alcohol ; and euro - american reacted more to wind . in terms of symptomology , statistically significant increase in recurrent itching on the face was noted in the asian population , and fewer euro - american avoided certain cosmetics due to skin reactivity .
these findings were supported in a critical literature review , which showed that the evidence supporting the ethnic difference hypothesis using objective tests rarely reaches statistical significance and is often biased by subjective endpoints .
recent data looking into age - related differences in hyperreactivity are showing more consistent results .
whorl performed patch testing with 34 irritants on 2776 patients and found that young patients were more reactive than old patients .
robinson 's findings also corroboratedthe trend towards increased reactivity in the young subjects compared to the old subjects .
the mechanism leading to the sss has been debated in the literature , but the leading hypothesis relates to increased stratum corneum permeability .
there is a known inverse relationship between corneocyte size and stratum corneum thickness and the permeability of the skin , and changes in this mechanical barrier result in abnormal skin penetration by irritants .
in addition , low levels of ceramides in the stratum corneum have been linked to increased severity of sls - induced irritant contact dermatitis , pointing toward barrier compromise in sensitive skin .
seidenari linked self - reported hyperreactivity to decreased skin capacitance ( indicating decreased water content ) , objectively suggesting increased absorption of irritants by the sensitive - skin population . in the same study ,
increased erythema was objectively measured in hyperreacting subjects suggesting involvement of some baseline vascular component , and leading more recent investigators to propose the involvement of cutaneus sensory innervation in the pathogenesis of sss .
as with many syndromes , the management scheme presented here emphasizes the diagnostic framework [ table 1 ] .
the clinical approach to the sss demands a thorough process of eliminating obvious as well as more subtle diagnoses .
once the diagnosis is made , deriving the appropriate treatment becomes a relatively simple task .
note that since much of the mechanisms of sss are unknown , the clinician must be comfortable with a certain degree of ambiguity and uncertainty . underlying mechanisms of sensitive skin syndrome it is reasonable to organize the differential diagnosis by dividing sss into visible and invisible sss .
some dermatoses that most clinicians find simple to diagnose may have atypical presentation and as a result lack the  expected morphology .
eczema , atopic dermatitis , and rosacea are likely the three most common causes of sss related to barrier defect .
full discussion of these conditions is beyond the scope of this overview but we will highlight some common clinical features .
careful history , including family history and occupational history , combined with a detailed physical exam will often reveal the diagnosis . in the history
particular consideration should be given to culprits such as the masking effect of other topical agents applied by the patient .
the physical exam should include scrutiny of the face and scalp for subtle signs of minor inflammation , which are often masked in sss with underlying endogenous dermatoses . in all of these conditions
the patients are likely over - exfoliating their skin and thus exacerbating the barrier dysfunction . therefore ,
following specific treatment to halt the acute pathological process , preventing recurrence with a proper skin care regimen is indicated . in eczema and atopic dermatitis , the careful clinician may resort to short - term ( 2-week ) use of corticosteroids to stop the inflammatory process .
calcineurin inhibitors are alternatively indicated for delicate areas on the face . in an effort to control histamine release in atopic dermatitis
, antihistamines can be added and a relatively allergen - free environment should be created . in rosacea , the mainstay of treatment is oral and topical antibiotics . in seborrhoeic dermatitis , azoles are the mainstay of treatment and low potency corticosteroids and emollients can be added acutely to treat the inflammatory process .
contact dermatitis ( cd ) and photocontact dermatitis ( pcd ) , as well as nonimmune contact urticaria ( nicu ) and immune contact urticaria ( icu ) , are all conditions that may elicit sss symptomology , with transient objective findings on physical exam .
allergen - free products are now available and should be included as part of further skin care regimen in these patients .
the main reason why nicu is often a missed diagnosis in patients presenting with the sss is the transient nature of the reaction .
thus , after testing with small amounts of product on the skin , the patient should be carefully examined using minimal magnification : the lesions will be typically revealed within 20 minutes .
common trigger agents are fragrances ( e.g. cinnamic aldehyde ) and preservatives such as sorbic and benzoic acids . once triggers
icu can be demonstrated with open and occluded testing , followed by prick testing with appropriate positive and negative controls if no response is elicited .
various foods , latex , parabens , and other chemicals have been implicated in the causation of icu .
however , there are cases in which no clinical clue is provided by the physical exam . in these cases , a 2-week trial of appropriate - strength corticosteroid may solve the mystery by pointing to an eczematous process in the case of symptoms resolution .
nonetheless , the careful clinician should consider avoiding prolonged use of topical corticosteroids since there is anecdotal clinical experience of topical corticosteroids inducing sss and , at least in the case of barrier dysfunction , earlier and complete steroid tachyphylaxis has been demonstrated .
if no symptomatic relief is observed , the patient 's sss is likely due to an invisible underlying cause .
both of these cases defined by maibach , no signs are present or can be elicited on the skin . in objective irritation
the mechanism is unknown and this diagnosis likely bundles more than one pathological process in it . interestingly ( and clinically frustratingly ) , maibach considers subjective irritation to be the most common cause of cis .
finally , body dysmorphic disorder ( bdd ) should always be considered by the dermatologist when assessing skin complaints without objective findings .
a recent cross - sectional study found a prevalence of 14% among patients in a cosmetic dermatology clinic . in the context of sss
, dermatologists should be aware that facial irritation complaints without any findings on exam are a common presentation in the dysmorphic patients and therefore extra caution is warranted .
referral to a mental health professional is indicated since these patients are at risk of suicidal behavior .
maibach notes that patients suspected of having bdd often require a detailed diagnostic process in order to build the trust needed to safely refer them to the mental health professional . table 2 summarizes the steps in the evaluation of a patient suspected to have sss .
specific algorithms have been developed for the management of sss but they are the result of accumulated clinical experience and lack experimental evidence to support their use . nonetheless , algorithmic thinking may aid in ensuring complete assessment .
these algorithms include four basic steps : discontinuation , assessment , testing , and slow re - introduction .
discontinuation of all topical medication and/or products , as well as elimination of activities and clothing resulting in skin friction , should be initiated and may need to last up to 12 months . the patient should then be assessed ( as described above ) for the occurrence of any visible dermatoses . if no clear pathology has emerged , rigorous testing is the next step .
testing should include patch and photopatch testing of routine allergens as well as of all of the patient 's skin care items .
specific testing for contact urticaria should be a part of the testing protocol . finally ,
the next step in management is slow re - introduction of the  minimally necessary skin care products . for females ,
recommend adding low - allergenic- potential cosmetic products one at a time in the following order : lipstick , face powder , and blush .
for all products re- introduced , recommend testing by applying the product to a 2-cm area lateral to the eye for five consecutive nights and documenting the positive and/or negative result .
this exhausting process is not only a rational solution from a clinical management standpoint but may also aid in diagnosing the specific culprit in cases of invisible sss .
understanding the underlying mechanisms may lead to the development of a well - standardized screening test .
this will allow clinical studies to rely on objective findings rather than self - reports and this , in turn , may result in more comprehensive and efficient management strategies .
female self - perception of sensitivity is consistently increased compared to that of males , yet when put through objective reactivity testing the trend is unclear .
it is reasonable to organize the differential diagnosis by dividing sss into visible and invisible sss .

Answer:
sensitive skin syndrome ( sss ) is a common and challenging condition , yet little is known about its underlying pathophysiology .
 patients with sss often present with subjective complaints of severe facial irritation , burning , and/or stinging after application of cosmetic products .
 these complaints are out of proportion to the objective clinical findings . defined as a self - diagnosed condition lacking any specific objective findings
 , sss is by definition difficult to quantify and , therefore , the scientific community has yet to identify an acceptable objective screening test . in this overview
 we review recent epidemiological studies , present current thinking on the pathophysiology leading to sss , discuss the challenges sss presents , and recommend a commonsense approach to management .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
laparoscopic cholecystectomy with three or four ports is the standard operation for gallbladder diseases worldwide .
the established use of 5 or 10  mm instruments and ports leads to small skin incisions in the upper abdominal wall .
however , these scars are still visible and might be a potential risk factor for incisional hernia or adhesions .
furthermore , new innovative methods such as notes ( natural orifice transluminal endoscopic surgery ) show promising first results regarding the technical feasibility and the possibility of scarless and painless operation [ 14 ] . at the present time
, it becomes more important for younger patients to undergo surgery with none or at least very small scars .
notes surgery might be the solution but is in case of transvaginal access to the abdominal cavity limited to female patients , and the procedure is not as easy to learn .
in addition , this technique requires special instruments , which do not exist in a regular department of surgery .
but due to the discussion about notes , another approach for the treatment of both genders is getting more attention from the public .
the transumbilical access , described in the literature amongst others as laparoscopic single - site surgery ( less ) [ 5 , 6 ] . for this technique ,
a 15 to 20  mm incision is made direct through the umbilicus , which is defined as a natural embryonic scare , and , therefore , the procedure is also called e - notes ( embryonic natural orifice transumbilical endoscopic surgery ) . beside the positive cosmetic effect of transumbilical incision , less incisional
this report describes our experience with single - incision cholecystectomies in 220 patients as standard procedure using a commercial available single - incision and conventional straight instruments .
as far as we know , this is the largest series about single - incision surgery as standard procedure .
between september 2008 and march 2010 , 220 laparoscopic single - incision cholecystectomies were performed at the  vivantes klinikum am urban  , berlin , germany by three experienced surgeons in standard technique .
single - incision operation using two 5  mm and one 10  mm trocar was performed in 24 patients ( 11% ) between october 2008 and january 2009 .
patients with symptomatic acute and chronic gallbladder disease were included in the observation , and all operations were performed consecutively .
exclusion criteria for single - incision surgery were patients with gallbladder perforation , diagnosed in ultrasound or ct scan , with peritonitis or severe critical illness . all patients were hospitalized for at least two days and were completely informed about the single - incision technique .
both arms are rolled out and the monitor is placed on the opposite site of the surgeons near the right shoulder . the operation begins with a longitudinal incision direct through the umbilicus between both umbilical edges ( approximately 1.5 to 2  cm ) . for a clear and safe closure of the linea alba at the end of the operation , the umbilicus has to be disconnected from the ground with a scissor .
after good exposure of the linea alba with small hooks , the fascia has to cut with a scissor at a length of 15 to 20  mm . after dissolving of eventually existing adhesions with fingers ,
a langenbeck`s hook has to retract the inferior part of the incision and the single - port ( triport , olympus , germany ) can be safely brought into the abdominal cavity with the triport injector introducer . after establishing the pneumoperitoneum up to 14
mm hg with co , a 30 5 or 10  mm laparoscope was used for initial inspection of the abdominal cavity at a 1520 reverse trendelenburg , right - side - up position .
we used as instruments conventional straight 5  mm graspers and a 5  mm hook electrocautery device .
because of the gel valves , a continuous grease of the instruments ( instellagel , farco - pharma gmbh , germany ) is important for a safe , nonfitful handling .
a special technique for a better movement inside the abdominal cavity is cross - handedness of the instruments .
that means to undercross the instrument in the left hand under the instrument in the right hand . for a right hander
the right hand holds the gallbladder with a grasper , and the hilum was prepared with a hook electrocautery device to expose the cystic duct and cystic artery .
both structures were clipped with a 5  mm endoscopic clip applier ( ligamax m / l , ethicon endo - surgery , oh , usa ) and divided with scissors .
after dissection the gallbladder from the fossa , the bladder was removed through the triport system without an endobag ( figure 1 ) .
the fascial incision was closed with a nonabsorbable 0 suture ( prolene , ethicon , germany ) .
finally , skin closure was done with an absorbable 4/0 suture ( monocryl , ethicon , germany ) .
comparison of the umbilicus before ( figure 2(a ) ) transumbilical incision and at the end of the operation ( figure 2(b ) ) demonstrates that the incision is only at the ground of the umbilicus .
the mean age of 142 females ( 65% ) and 78 males ( 35% ) was 47 years ( range : 1589 ) , and an elective surgery was planned for 154 patients ( 70% ) .
the average american society of anesthesiologists ( asa ) classification was 2 ( range : 13 ) and the body mass index ( bmi ) 28 ( range : 1549 ) . mean hospital stay was 4 days ( range : 220 ) and 103 patients ( 47% ) had secondary diagnoses .
thirty - seven patients ( 17% ) presented preoperative bile duct stones and of all received an endoscopic retrograde cholangiography ( erc ) .
twenty - three patients ( 10% ) had clinical signs of biliary pancreatitis in medical history .
preoperatively measured laboratory values were in a regular range for leucocytes , c - reactive protein ( crp ) , aspartate aminotransferase ( ast ) , alkaline phosphatase ( ap ) , and bilirubin .
all patients received the same prophylactic antibiotic treatment of 2  g cefotaxim and 0.5  g metronidazol as single - shot dosage .
mean operation time was 62 ( range : 26174 ) minutes , and 31 patients ( 14% ) had an incidential umbilical hernia .
twenty - two patients ( 10% ) had previously undergone abdominal operation , and 54 patients ( 24% ) showed peritoneal adhesions .
three patients ( 2% ) required conversion to a three - port technique because of a very large gallbladder with deep positioned hilus .
an exact identification of the structures in the hilum via single port was not possible .
one patient had a severe bleeding out of the cystic artery after the first clip was accidentally removed .
a wound drainage was positioned at the end of operation in five cases ( 3% ) .
one patient developed a 2  cm necrosis of the bile duct after mirizzi 's syndrome , two days after the initial operation .
of 220 patients , 202 ( 92% ) had gallbladder stones and 150 patients ( 68% ) multiple stones .
signs of gallbladder inflammation was diagnosed in 218 patients ( 99% ) , and 57 ( 26% ) patients had an acute cholecystitis .
the classification of inflammation grade was in 74 patients ( 34% ) light , 101 patients ( 46% ) moderate and 45 patients ( 20% ) severe .
a gallbladder hydrops was noted in 53 patients ( 24% ) , and ten patients ( 4.5% ) developed a shrunked gallbladder .
we could demonstrate in one of the largest series that single - incision cholecystectomy is feasible and safe as standard technique for elective and acute gallbladder disease .
most patients in our collective were satisfied with an almost scarless procedure and less pain after operation .
previously published studies about multiport technique which included more than 1000 patients showed similar results compared to our study group [ 911 ] .
the conversion rate to an open procedure was in former studies between 2% and 7% and in our population only 1% .
major complications in multiport surgery such as bile duct or vessel injury were noted in 0.9% to 5.8% of all patients . although we had a comparative high complication rate of 5% , major complications like bile duct injury and necrosis happened only in two patients ( 1% ) , which is within the international standard .
while single - incision surgery is getting more and more popular , patient numbers of previously published reports are still low [ 1219 ] .
a review of eight studies from 2009 about single - incision cholecystectomy shows only two studies with 100 patients [ 14 , 17 ] , and the largest series of single - incision surgery , published by lee et al .
one of the most important points in the discussion about notes or single - incision surgery is the extended operation time , because of a more complicated access to the abdominal cavity and the difficult handling of the instruments .
the mean operation time in eight studies about less surgery including 365 patients was 80 minutes ( range : 5194 ) [ 1219 ] .
but it is mentionable that studies with a higher case number like rivas et al . and
one reason might be that the learning curve for this technique is certainly longer as for the three- or four - port technique .
rivas et al . compared in their study including 100 patients the first 50 patients with the second 50 ones .
age and bmi were almost equal , but the operation time was considerable reduced from 73 to 45 minutes .
our mean operation time was 64 minutes , and it is still close to the regular time for conventional laparoscopic cholecystectomy .
however , we had a high percentage of patients with acute cholecystitis compared to other studies with 5% and 9% [ 14 , 15 ] .
a partition of our 220 cases into patients with acute and chronic cholecystitis showed a considerably different operation time .
fifty - seven patients with acute cholecystitis required a mean operation time of 80 minutes ( range : 34174 ) and in contrast patients with chronic cholecystitis or no inflammation only 57 minutes ( range : 28159 ) .
in addition , we could not indicate a reduction of operation time between the first 50% of operations and the second 50% like rivas et al .
we performed the operation in the first 110 patients in a median time of 61 minutes and the second 110 patients in a median time of 65 minutes .
it seems that the learning curve has an important impact but is for an experienced laparoscopic surgeon not as important in large series .
but one reason for the more extended time in later operations might be the different view on the indication for single - port surgery after a major experience .
the first 30 patients had not undergone previously abdominal surgery and , therefore , the operation easier to perform with a reduced operation time .
another important point of criticism about single - incision surgery is the conversion rate to multiple ports .
several studies reported about a conversion rate between 0% and 5% and are similar to our results with 2% [ 1316 , 18 , 19 ] .
only one study of lee et al . had a high conversion rate of 13.5% because of technical difficulties .
conversion rate to an open procedure was 1% in our study group and is described in the literature with 0% to 2% [ 1316 , 18 , 19 ] .
we had to convert to an open procedure because of an acute bleeding from the cystic artery without an identifiable vessel in the hepatoduodenal ligament .
a blind closure of the vessel with 5  mm clips or bipolar thermocoagulation could have injured structures in the ligament .
the second patient had an unknown cholecystoduodenal fistula , which could not be closed in laparoscopic technique .
considering these results , the conversion rate in single - incision surgery is even to multiport standard .
a view on the complication rates after single - site surgery in the literature shows a percentage between 0% and 5,4% [ 1219 ] .
four studies reported about no complications in their study population [ 13 , 14 , 18 , 19 ] . in our study , eight patients ( 5% ) developed postoperative complication , and six of these patients ( 3.5% ) had to undergo reoperation . except romanelli et al . , who had one case of postoperative hernia , other reports did not mention a reoperation .
an analysis of our six patients showed that one of two patients with an incisional hernia had an incidential umbilical hernia and might have used a mesh for optimal wound closure .
two patients developed a wound infection , and a wound debridement had to be performed in both cases .
in one patient , the gallbladder was opened for extracting the stone and that might be the reason for infection .
if the use of an endobag is more safely for preventing wound infection is questionable .
we did not use one endobag in our series and had only an infection rate of 1% .
these infections would have healed secondary , but because of a good cosmetic result , we decided to reoperate the patient .
these hernias could be safely repaired within the standard closure of the fascia using a nonabsorbable suture . in conclusion
, we could demonstrate for the first time that laparoscopic single - incision cholecystectomy as standard procedure is feasible and safe compared to conventional multiport technique .
beside scarless operation , one major advantage in comparison to notes is the treatment option for both genders and the use of conventional instruments .
results of long - term followup have to answer the theoretical increased risk of incisional hernia .

Answer:
background and aims .
 we describe our experience of performing transumbilical single - incision laparoendoscopic cholecystectomy as standard procedure for acute and chronic gallbladder diseases . methods . between september 2008 and march 2010 , 220 patients underwent laparoscopic single - incision surgery . a single port was used for 196 patients and two conventional 5  mm and one 10  mm port in 24 cases .
 all operations were performed with straight instruments .
 results .
 single - incision surgery was successfully performed in 215 patients ( 98% ) .
 three patients ( 1.4% ) required conversion to a three - port technique and two patients ( 0.9% ) to an open procedure .
 average age of 142 women ( 65% ) and 78 men ( 35% ) was 47 years ( range : 1589 ) , average asa status 2 ( range : 13 ) and bmi 28 ( range : 1549 ) .
 mean operative time was 62 minutes ( range : 26174 ) and 57 patients ( 26% ) had histopathological signs of acute cholecystitis .
 eleven patients ( 5% ) developed to surgery - related complications and nine ( 4% ) of these required a reoperation .
 the mean followup was 331.5 ( range : 11590 ) days .
 conclusion .
 transumbilical single - incision cholecystectomy is a feasible and safe new approach for routine cholecystectomy . after a short learning curve , operation time and complication rate are comparable with standard multiport operation .
 in addition , most cases of acute cholecystitis can be performed with this technique .


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
A Designed Functional Metalloenzyme that Reduces O2 to H2O with Over One Thousand Turnovers

Paper sections:

Much progress has been made in designing metalloproteins with structures similar to native enzymes[1] and advances in computational biology have allowed for rational design of function as well[2]. Despite these achievements, most designed enzymes have simple active site structures and low activities with limited turnover numbers. Designing artificial enzymes with higher complexity and numbers of turnovers is not only an important measure of success in the field, but can also reveal structural features responsible for tuning enzymatic activities and may result in artificial enzymes for practical applications. A primary example of a complex metalloenzyme with an important function is the family of terminal oxidases, such as heme-copper oxidases (HCOs)[3] and bd oxygen reductases[4], which catalyze the kinetically difficult reduction of O2 to water and, in doing so, generate the transmembrane proton gradient that drives important processes such as ATP synthesis. While many catalysts that reduce oxygen to water have been reported[5], a long-standing challenge is to carry out the reaction without the production of reactive oxygen species (ROS), such as superoxide and peroxide, under mild conditions. ROS not only damage biomolecules in cells and components in fuel cells, but also decrease energy efficiency, as ROS are a result of incomplete catalysis. In addition, efficient catalysts using non-precious metal ions such as iron or copper will greatly decrease costs in practical applications[6]. Therefore, designing enzymes that catalyse complex reactions, such as oxygen reduction, at mild pH that are based on small, stable, and easy to produce scaffold proteins, would yield ideal models for studying the fundamentals of this chemistry and produce useful catalysts for applications such as fuel cells.

In HCOs the active site responsible for O2 reduction is a heterobinuclear metal center containing a heme-Fe and a His-ligated Cu (CuB). We have previously reported the introduction of two histidines in the heme pocket of sperm whale myoglobin (swMb) through Leu29His and Phe43His mutations[7], which, together with the native distal His64 formed a copper binding site (this mutant is called CuBMb, see Supporting Information, Figure S1A). As purified, CuBMb has no metal in the CuB site (designated as E-CuBMb; i.e. empty). Introducing the copper binding site into myoglobin transformed it from a simple oxygen carrier into a copper-dependent heme oxygenase at pH 8[8], which degrades the heme cofactor to verdoheme. Since the active site Tyr in native HCOs has been shown to be critical to the function of these enzymes[9], we hypothesized that the lack of a tyrosine next to one of the histidine ligands in copper loaded CuBMb (Cu-CuBMb) may limit conversion of O2 to water. Herein, we report the introduction of a Tyr at two different positions close to the histidines of the putative copper binding site of CuBMb and demonstrate that these artificial enzymes are able to efficiently reduce O2 to water, one with over 1000 turnovers, and with minimal release of superoxide or peroxide. These results demonstrate that both the presence and positioning of the tyrosine is important for terminal oxidase activity.

Since the design and activity of the CuBMb mutant were first reported[7–8], the crystal structure of E-CuBMb has been solved; the histidine ligands in this structure overlay well with those of bovine HCO (PDB 1V54) (see Supporting Information, Figure S1A) and this structure was used to guide the placement of Tyr in the active site pocket[11]. Since Tyr244 is four residues away from His240 in the primary sequence of bovine HCO, we first placed an analogous Tyr four residues from His29 via a Phe33Tyr mutation (called F33Y-CuBMb). The crystal structure of E-F33Y-CuBMb shows excellent agreement with the computer model (Figure S1B). A crystal structure of Cu-F33Y-CuBMb has also been obtained (Figures S1 and S2). However, although Tyr33 points into the Cu-binding site and is next to His29, Tyr33 does not overlay well with Tyr244 of bovine HCO (Figure 1A). To find a better structural overlay, a recent crystal structure of a cbb3 HCO[10] revealed that the Tyr can be near the His ligand spatially, while not necessarily close in the primary sequence. Therefore, we alternatively modelled Tyr next to His29 through a Gly65Tyr mutation (called G65Y-CuBMb). The energy-minimized computer model of E-G65Y-CuBMb overlays very well with that of cbb3 HCO (Figure 1B).

The spectral properties of oxidized and reduced states of these variants are similar to those of wild type swMb (WTswMb)[12] (Supporting Information, Figure S4). However, upon exposure of the ferric- states of both E-F33Y-CuBMb and E-G65Y-CuBMb to excess reductant (ascorbate with N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD) as a mediator) in air saturated buffer in a sealed cuvette, a transition from ferric through oxy to deoxy was observed (Supporting Information, Figure S4E–F), which is in contrast to WTswMb (Supporting Information, Figure S4D), and prompted an investigation of the product of this reduction.

To confirm that the product of oxygen reduction is water, 17O NMR was carried out. Production of H217O above the background level (natural abundance) of H217O in water was monitored in a sealed vessel containing 17O2, the myoglobin variant, and excess reductant, using 17O-labeled Tyr as an external standard. A typical 17O NMR spectrum is shown in Supporting Information, Figure S5. Figure 2 shows the ratios of the H217O peak area to 17O-Tyr peak area at various time points after addition of 17O2 to initiate its reduction by WTswMb, E-F33Y-CuBMb, and E-G65Y-CuBMb, normalized to the area of the peak before initiating the reaction. The normalized ratio of water in the WTswMb sample remains close to 1, suggesting that the protein did not produce any new H217O. In contrast, E-F33Y-CuBMb and E-G65Y-CuBMb produced up to 10 mM H217O at 120 min, as indicated by an increase in the normalized ratio, confirming the production of water.

The rates of oxygen reduction were measured quantitatively using an O2 electrode to monitor the concentration of O2 over time in the presence of reductant, similar to protocols reported for native HCO[13]. The rate of O2 disappearance was measured for WTswMb and the CuBMb variants (Supporting Information, Figure S6). A hallmark of native terminal oxidases is the clean reduction of O2 to water with minimal release of superoxide or peroxide[14]. To identify the product (O2−, O22−, or H2O) we employed superoxide dismutase (SOD) and catalase which selectively react with superoxide and peroxide, respectively, producing O2 as one of the products, which would slow the apparent rate proportional to the amount of ROS released. By comparing the rates of reduction in the absence of and in the presence of SOD and catalase, the portion of O2 reduction due to water formation (in blue) and due to superoxide or peroxide formation (in red) can be calculated (see Figure 3A, and Supporting Information Table S5 and Supporting Text). Not surprisingly, most of the O2 consumption rate by WTswMb is due to superoxide or peroxide formation, consistent with autoxidation[15] and these rates remain unaffected in the presence of Cu2+, Zn2+ or Ag+. Interestingly, introducing two histidine residues into the distal pocket of WTswMb results in substantial inhibition of superoxide/peroxide formation in comparison to WTswMb, but does not significantly contribute to water formation, and therefore results in a decrease in the overall rate of O2 consumption. Similar to WTswMb, addition of Cu2+, Ag+ or Zn2+ to E-CuBMb does not perturb the rate and product of O2 reduction. In contrast to both WTswMb and CuBMb, introducing a Tyr next to the one of the His ligands at either position 33 or 65 results in a dramatic increase in water formation and overall rate of O2 consumption. The rate of water production increases up to 4.2 and 1.1 µM/s when using 18 µM E-G65Y-CuBMb and E-F33Y-CuBMb, respectively. To our knowledge, this is the first time that Tyr and its specific positioning has been shown to play an important role in directing the product of O2 reduction to water formation instead of release of superoxide or peroxide. Under further optimized conditions (with a higher concentration of reductant), the rate of O2 reduction to water by E-G65Y-CuBMb is 28 min-−1 (Supporting Information, Figure S10) – within ~150 fold of native HCOs[16]. Additionally, we show in Supporting Information, Figure S7 that 1.8 mM and 18 mM cyanide, a known inhibitor of HCO activity, inhibits the activity of E-G65Y-CuBMb and E-F33Y-CuBMb, respectively.

Surprisingly, the O2 reduction activity is independent of the presence and identity of the metal in the engineered CuB site (Figure 3A). To further support this finding, we repeated the studies with varying equivalents of copper (0–2 equivalent) as well as a strong metal chelator, ethylenediaminetetraacetate (EDTA), but no further change was noticed (Supporting Information, Figure S8). As E-G65Y-CuBMb is still ~150 fold lower in activity than HCOs,[16] our results are not intended to rule out the role of copper ion native HCOs. Alternatively, these results do indicate that a copper center is not strictly necessary for oxygen reductase chemistry and are consistent with recent discovery of bd oxygen reductases[4] that lack the CuB center and yet can still perform the oxidase activity.

More importantly, this study demonstrates the importance of the presence and positioning of tyrosine in the active site. In both types of native oxidases the reaction is either known or proposed to proceed by the critical steps of two electron reduction of the oxygen to a peroxo intermediate, followed by rapid protonation and heterolytic O-O bond cleavage, leading to a transient ferryl intermediate; it is also proposed that the conserved tyrosine in HCOs is involved in donating an electron.[3–4] To elucidate the potential role of the Tyr, we have obtained the crystal structure of E-F33Y-CuBMb. When comparing with E-CuBMb and E-F33Y-CuBMb with WTswMb, we found that introducing two histidine residues and then an additional tyrosine residue has led to stabilization of two and three water molecules, respectively, in the distal pocket (Supporting Information, Figure S11), in comparison to one water molecule in the distal pocket of WTswMb. In addition, where WTswMb has only one hydrogen bond partner available to interact with the bound oxygen (H64), two and three more hydrogen bonding capable residues are available in E-CuBMb and E-F33Y-CuBMb, respectively. Studies of crystal structures of various states of HCOs have suggested a role for water molecules and an extended hydrogen bonding network in the oxygen reduction step[17], and computational studies[18] of HCOs have supported the role of similar interactions in oxidase activity. Based on these studies, we propose that tyrosine and its associated hydrogen-bonding network works to activate the ferric-superoxo state of our designed enzymes and this activation allows it to accept a second electron from the exogenous reductant towards complete reduction to water. Further studies are underway to elucidate the exact role of Tyr in our model protein system.

Finally, to test the extent of the functional activities, we have carried out multiple turnover reactions. To a solution containing E-F33Y-CuBMb or E-G65Y-CuBMb and excess reductant, ~500 µM (28 equivalents) O2 was added repeatedly and each time the total O2 consumption was monitored using an O2 electrode. These stepwise additions resulted in the multiple plateaus observed in Figure 3B. We calculate that E-F33Y-CuBMb and E-G65Y-CuBMb achieved >505 and > 1056 turnovers, respectively (Figure 3B, inset).

In summary, we have demonstrated the first successful design of a functional protein capable of cleanly reducing oxygen to water with minimal release of superoxide or peroxide, similar to the activity of terminal oxidases, with more than 1000 turnovers. Through these designed functional proteins, we have also shown that Tyr next to one of the copper coordinating His ligands plays a critical role in directing O2 reduction to water formation. Furthermore, the positioning of this Tyr is critical for affecting the rate of catalysis. Even though the designed proteins are still less active than terminal oxidases, it is remarkable that oxygen reduction to water was conferred to a much smaller protein, myoglobin, with only three mutations of the distal pocket. Given their high enzymatic turnovers, smaller size, higher stability, and higher expression yield, these designed enzymes will serve as ideal models for a more detailed understanding of terminal oxidases and allow for potential applications in biology and alternative energy.

Answer: Summary Rational design of functional enzymes with high turnovers is a significant challenge, especially those with complex active site and difficult reactions, such as in respiratory oxidases. Introducing 2 His and 1 Tyr into myoglobin resulted in designed enzymes that reduce O2 to H2O with > 1000 turnovers and minimal release of reactive oxygen species. This also showed that presence and positioning of Tyr, not Cu, are critical for activity.


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
klippel - trenaunay syndrome ( kts ) is characterized by the triad of port wine stain , venous and lymphatic malformation , and soft tissue hypertrophy of the affected extremity .
depending on the type of vessel involved and its flow characteristics kts is classified as a slow flow complex combined capillary venous or capillary venous lymphatic malformation .
the localized variants are solitary angiokeratoma , fordyce 's angiokeratoma , angiokeratoma of mibelli and angiokeratoma circumscriptum naeviforme ( acn ) .
the systemic form , angiokeratoma corporis diffusum , is usually associated with an inborn error of metabolism . among all the types , acn is the rarer and the only congenital variant of angiokeratoma .
the lesions of acn are bluish red , well defined and are classically seen on the lower extremity in a unilateral distribution .
a 4-year - old male child presented with complaints of a linear eruption on his right leg since birth .
his parents gave history of pain and several episodes of bleeding from the lesion after trauma .
, there were multiple hyperkeratotic discrete and closely aggregated papules and plaques of varying size on an erythematous base arranged linearly along the lateral aspect of the right thigh extending up to the knee joint [ figures 1 and 2 ] .
right lower limb arteriovenous ( av ) doppler revealed a hypoplastic right lower limb deep venous system with compensatory dilatation of the superficial venous system .
the superficial femoral vein , popliteal vein , anterior tibial and posterior tibial vein on right side were hypoplastic along with thickening of subcutaneous tissue and associated dilatation and malformation of the superficial venous system [ figures 5 and 6 ] .
histological examination revealed numerous dilated thin walled , congested capillaries mainly in the papillary dermis and very few in reticular dermis .
overlying epidermis showed compact hyperkeratosis , irregular acanthosis with elongated rete ridges consistent with diagnosis of angiokeratoma [ figures 7 and 8 ] . on the basis of clinical , histological and radiological findings
dilated superficial venous system verrucous plaque with soft tissue hypertrophy prominent superficial veins on dorsum of foot plain radiograph showing soft tissue hypertrophy magnetic resonance imaging angiography showing dilated superficial veins on the right side dilated superficial venous system hyperkeratotic epidermis with congested capillaries in papillary dermis with normal deep dermis and subcutaneous tissue hyperkeratotic epidermis with dilated congested capillaries in papillary dermis
in 1900 , two french physicians maurice klippel and paul trenaunay described two patients with hemangiomatous lesions of the skin with associated bone and soft tissue hypertrophy and coined the term naevus variqueux osteohypertrophique . in 1907 , parkes weber reported the association of kts with av fistula and called it hemangiectatic hypertrophy . in 1965
, lindenauer proposed that the syndrome originally described by klippel and trenaunay without av malformation be considered as a specific entity the kts and the one associated with av fistula be designated as parkes weber syndrome . in a study of 252 patients with kts at the mayo clinic , 63% had all three features of kts .
port wine stains were found in 98% of patients , venous malformations in 72% and limb hypertrophy in 67% patients .
the port wine stain is apparent at birth and usually involves the affected limb , often stopping at the midline with a sharp linear border .
the nevus may involve the whole of one side of the body and may sometimes be present on the contralateral limb .
varicose veins may be obvious at birth , but frequently become evident after walking starts .
the venous abnormalities of the deep venous system that occur in kts include aneurysmal dilatation , duplication , aplasia , and hypoplasia .
patients with at least two of the three cardinal features have been classified as having an incomplete form of kts .
it is the only congenital variant and is more common in women and is usually unassociated with systemic disease .
the histopathological finding is same irrespective of the type of angiokeratoma and consist of numerous thin walled congested capillaries mainly in the papillary dermis underlying an epidermis that shows variable degree of acanthosis with elongation of rete ridges and hyperkeratosis .
unusual variants of acn described in literature are along the lines of blaschko , and a systematized band like pattern .
verrucous hemangioma clinically resembles angiokeratoma but they can be differentiated histopathologically as the former involves the dermis and the subcutaneous fat and the latter involves only the dermis .
our case showed typical clinical features of acn , which was confirmed by histopathologic examination .
associated soft tissue hypertrophy and deep venous malformation on mri are classical features of kts .
there are very few case reports of association of kts with acn in world literature .
schimpf and wehberg in their study have reported three cases of acn on the lower limb associated with soft tissue hypertrophy .
bone hypertrophy was present in two cases , varicose veins in one case and only one case had associated port wine stain on the back .
the case reported by odeh had acn of the right leg associated with soft tissue hypertrophy and bone hypoplasia of the right half of pelvis .
they preferred the term hemangiectatic hypertrophy as there was no associated bony and venous abnormalities of kts .
to the best of our knowledge , this is the first case report of this rare association from india .

Answer:
klippel - trenaunay syndrome ( kts ) is a cutaneous capillary malformation on a limb in association with soft tissue swelling with or without bony hypertrophy and atypical varicosity .
 the capillary malformation associated with kts is port wine stain .
 angiokeratoma circumscriptum naeviforme ( acn ) is a congenital variant of angiokeratoma commonly present on the lower limb as a hyperkeratotic plaque .
 acn is rarely associated with kts .
 we report a case of acn with soft tissue hypertrophy and deep venous malformation ( possibly a variant of klippel - trenaunay ) in a 4-year - old male child .


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
Imide arylation with aryl(TMP)iodonium tosylates

Paper sections:

This article is part of the Thematic Series "Hypervalent iodine chemistry in organic synthesis".

Introduction

Imides are important structural units in a range of approved pharmaceuticals and agrochemicals (Scheme 1a) [1]. Despite the general prevalence of imides, N-aryl imide derivatives are relatively rare in such compounds. We were surprised by this disparity, but found that a lack of methods to synthesize N-aryl imides may explain their scarcity; this is particularly true relative to other N-aryl compounds. The survey of methods revealed that the dominant approach to N-aryl imides is to employ aniline starting materials (Scheme 1b, left), as was done in the synthesis of pentoxazone and related herbicides [2]. The alternative aromatic substitution approach with imide anions (Scheme 1b, right) is hampered by their low nucleophilicity [3]. Therefore, transition metals feature prominently in such methods, but even recent examples employ stoichiometric metal mediators [4]. Metal-free methods by classic SNAr are also attractive, but only possible on very electron-deficient arene substrates [5]. Diaryliodonium salts are useful reagents for metal-free aryl transfer [6–10] and Muñiz and co-workers have recently reported an elegant study on sterically controlled C–N coupling of 2,6-disubstituted aryl(phenyl)iodonium salts and imides [11]. We have been investigating the generality of electronically controlled aryl transfer from aryl(trimethoxyphenyl)iodonium salts [12–14] and describe here the development of a C–N coupling of a phthalimide anion with non-sterically biased aryl groups. The protocol is compatible with ortho-, meta-, and para-substitution on the aryl group and the phthalimide moiety may also provide access to anilines.

Imides as an important scaffold.

Results and Discussion

We initiated our optimization of the arylation of the potassium phthalimide nucleophile with diaryliodonium electrophiles by surveying several reaction conditions: dummy ligand (Aux), counter anion, solvent and volume, reaction temperature, and stoichiometry (Table 1). Consistent with an electronically controlled aryl transfer, the trimethoxyphenyl (TMP) auxiliary was superior to mesityl (Mes), phenyl (Ph), and anisyl (An) auxiliaries under several different reaction conditions (Table 1, entries 1–3; 11 and 12; 16 and 17). While the counter anion did not exert a dramatic influence on the reaction yield, using tosylate (OTs) produced the highest yield in both DCE and toluene as solvent (Table 1, entries 4–8). Given our ability to readily access aryl(TMP)iodonium tosylate salts [12] we continued our optimization with these reagents. We observed a very narrow operating temperature with a maximum yield at 100 °C when toluene was used as solvent (Table 1, entries 9, 10, and 12). We also observed that the reaction yield decreases with dilution (Table 1, entries 13–15). Finally, the yield increases with increasing stoichiometry of phthalimide (Table 1, entries 10, 13, and 17). It is also important to note that under "optimal" conditions (Table 1, entry 17) we did not observe a Phth–TMP adduct. Moreover, we did observe essentially quantitative formation of TMP–I and therefore complete consumption of 1a and high fidelity for aryl transfer selectivity. At this time we are unable to account for the remaining mass balance (≈25%) of the methyl benzoate moiety of 1a. We have employed the conditions of entry 17 (Table 1) as our standard conditions to evaluate the scope of this reaction.

Discovery and optimization of reaction conditions.a

aConditions: 1 (0.1 mmol, 1 equiv), potassium phthalimide (see table for equivalents), solvent (see table), temperature (see table), 24 hours.

Results and Discussion

We have assessed the scope of compatible aryl groups under our optimal conditions (Scheme 2). Under electronic control, strong electron-withdrawing groups on the aryl ring lead to high yield of N-aryl phthalimide products (Scheme 2, 2a–d, 66–90% yield). However, the TMP auxiliary also enables the coupling of phthalimide with moderately electron-deficient aryl groups. For instance the p-chlorophenyl moiety (2e) is coupled to phthalimide in moderate yield (42%). Additionally, we have observed that electronic and steric effects operate in concert to couple an o-tolyl (2f) moiety to phthalimide in high yield (67%). In this case, 2,6-disubstituted aryl groups are not required for a sterically controlled coupling. Finally, as an example two polysubstituted aryl groups are introduced in this coupling reaction, which are specifically enabled by the use of an unsymmetrical aryl(TMP)iodonium electrophile (Scheme 2, 2g and 2h, 42 and 99% yield, respectively).

Scope of compatible aryl groups. Conditions: 1 (0.5 mmol, 1 equiv), potassium phthalimide (2.5 mmol, 5 equiv), toluene (2.5 mL), 100 °C, 24 hours. Isolated yields are reported.

Results and Discussion

The phthalimide moiety is well-recognized as an "NH3" surrogate, and the products depicted in Scheme 2 may be deprotected to yield aniline derivatives. In a specific example, 1a is reacted under modified conditions to yield 2a. In this one-pot procedure, hydrazine in aqueous ethanol is added directly to the reaction mixture and aniline 3 is isolated in 63% yield from 1a (Scheme 3).

One-pot synthesis of anilines.

Results and Discussion

We have previously described the coupling of aryl(TMP)iodonium tosylates with azide nucleophiles [14]. Azide is a notably stronger nucleophile than phthalimide and it is interesting to compare the reaction of these two nucleophiles with 1a under similar conditions (Table 2). The Mayr nucleophilicity constant of azide [15] is 20.5 and high yield (95%) is observed in a reaction with 1a under relatively mild temperature (65 °C) and short reaction time (2 hours, Table 2, entry 1). The Mayr nucleophilicity constant for phthalimide is five-orders of magnitude lower (15.5) [3] and under similar conditions leads to trace product (Table 2, entry 2). In order to obtain a high yield of 2a, albeit lower than given in entry 1, a higher temperature (100 °C) and a longer reaction time (24 hours) are required (Table 2, entry 3). This suggests that the contribution of nucleophilicity (via Mayr nucleophilicity constants) [16] may be useful in developing other coupling reactions with diaryliodonium electrophiles.

Comparison of nucleophilicity.

Conclusion

The coupling of both electron-deficient and sterically encumbered aryl groups with a phthalimide anion is achievable with aryl(TMP)iodonium tosylate salts. This is an electronically controlled coupling reaction that is enabled by the TMP auxiliary and complementary to the sterically controlled coupling previously reported. We anticipate that this reaction will find use as a starting point for the synthesis of N-aryl imides in a range of applications.

General experimental details, procedures, tabulated spectroscopic data, and 1H, 13C{1H}, and 19F NMR spectra of compounds 1g, 2a–i, and 3.

Answer: Herein, we describe the synthesis of N-aryl phthalimides by metal-free coupling of potassium phthalimide with unsymmetrical aryl(TMP)iodonium tosylate salts. The aryl transfer from the iodonium moiety occurs under electronic control with the electron-rich trimethoxyphenyl group acting as a competent dummy ligand. The yields of N-aryl phthalimides are moderate to high and the coupling reaction is compatible with electron-deficient and sterically encumbered aryl groups.