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:
Selective Recognition of d-Aldohexoses in Water by Boronic Acid-Functionalized Molecularly Imprinted Cross-Linked Micelles

Paper sections:

Carbohydrates are one of the most important classes of biomolecules and involved in numerous biological processes including cell–cell interaction, immune response, and viral and bacterial infection.1,2 Synthetic analogues of carbohydrate-binding lectins are powerful tools for the detection of biologically important sugars and intervention of carbohydrate-mediated interactions.3 Although receptors based on both covalent4-8 and noncovalent9-12 interactions have been reported, a general method for selectively binding carbohydrates in water remains elusive.13,14

As building blocks of oligo- and polysaccharides, the eight d-aldohexoses differ only in the stereochemistry of 1–3 hydroxyls. Unfortunately, the hydroxyl group is not a good functional group handle from the supramolecular viewpoint, because its strong solvation by water makes it difficult to use hydrogen bonds to bind a sugar. Having the same number of carbon and hydroxyls, the aldohexoses have only minute differences in hydrophobicity, mainly in the axial/equatorial distribution of the hydroxyls. Although the difference has been used successfully to distinguish glucose/glucoside from other monosaccharides,11,15 it is not clear how the other d-aldohexoses can be differentiated in this regard.

Despite these tremendous challenges, literature suggests boronic acid-based covalent receptors could potentially overcome the difficulty. Boronic acid-functionalized molecularly imprinted polymers (MIPs) were reported in the 1970s by Wulff as the stationary phase to separate sugar derivatives by chromatography.16 Monoboronic acids generally bind fructose more strongly than glucose due to its higher percentage of furanose that contains the preferred synperiplanar 1,2-diol for boronate formation.17 This selectivity, interestingly, could be reversed with diboronic acids preorganized to form boronate with the particular hydroxyls of glucose, whether the furanose or pyranose form.18-21 The preorganization comes from the organic scaffold whose structure and conformation dictate how the diboronic acids interact with its guests. Strongest binding is obtained when the maximum number of boronate ester bonds are formed with minimal strain.

The above results suggest that a general method to recognize carbohydrates might result if the number, distance, and orientation of boronic acids on the receptor can be tuned precisely to match the hydroxyl groups on the guest. Such structural control, however, is difficult to imagine given the minute structural differences of the carbohydrates.

Herein, we report that this level of structural precision can be readily obtained through covalent molecular imprinting within cross-linked micelles. The molecularly imprinted nanoparticles (MINPs) obtained practically could distinguish all eight d-aldohexoses based on the configurations of the hydroxyls. This work lays the foundation for the construction of receptors to bind more complex carbohydrates, since different hydroxyls contributed quite differently to the binding.

With a tripropargylammonium headgroup, surfactant 1 could be cross-linked in the micellar form on the surface by click chemistry with diazide 2 (Scheme 1), to afford alkynyl-functionalized surface-cross-linked micelles (i.e., alkynyl-SCM).22-24 Template 3 was solubilized in water together with DVB and a photoinitiator (DMPA) by 1 in the very beginning. It was prepared from 4-vinylphenylboroxine and glucose according a literature procedure.25 Because the diboronate product contains different isomers (e.g., 3a, 3b, etc.) that undergo transesterification during repeated crystallization, the material obtained from a single crystallization was used without further purification.26 After surface-cross-linking, azide 3 was added to decorate the resulting alkynyl-SCMs with a layer of hydrophilic ligands. Free radical polymerization was subsequently initiated by UV irradiation in the core to polymerize/cross-link the methacrylate of 1, DVB, and the polymerizible styrenyl groups of 3. The doubly cross-linked micelles were recovered by precipitation from acetone. Glucose was removed by repeated washing with acetone/water, methanol/acetic acid, and acetone.27 Template 3 has a free hydroxyl. As demonstrated previously, hydrophilic groups on the template anchor the template near the surface of the micelle/MINP and is helpful to its removal/rebinding.28,29

The MINP preparation was adapted from our published procedures.28-31 Cross-linking of the micelles and formation of the MINPs likewise were monitored by 1H NMR spectroscopy and dynamic light scattering (DLS), as shown by Figures S1 and S2 in the Supporting Information. DLS also allowed us to estimate the molecular weight of the nanoparticles. SCMs were characterized previously also by transmission electron microscopy (TEM) and mass spectrometry (after cleaving the surface-cross-linkages).22

To understand the potential of MINPs in carbohydrate recognition, we prepared boronic acid-functionalized receptors first for glucose, mannose, and galactose. Among the eight d-aldohexoses, these three are most biologically relevant, serving as building blocks for many naturally occurring oligo- and polysaccharides. We also prepared MINP(5), using the diboronate derivative of 4-nitrophenyl α-d-mannopyranoside 5 as the template. We are interested in the glycoside because the added hydrophobic aglycan potentially could contribute to the binding. In addition, the glycoside will be bound in the pyranoside form, different from the free sugars.

All the bindings were studied by isothermal titration calorimetry (ITC). The method previously was found to yield similar binding constants (Ka) as fluorescence titration for fluorescently labelled templates.28-31 As shown in Table 1, Ka between MINP(glucose) and glucose was 1.18 × 103 M−1 in 10 mM HEPES buffer at pH 7.4. This binding affinity compares favorably with those between lectins and their monosaccharide ligands (typically 103–104 M−1).1,2 Importantly, the MINP receptor displayed excellent selectivity, showing negligible binding toward other d-aldohexoses except allose (Ka = 0.52 × 103 M−1). Binding with selected non-aldohexoses was very weak, with Ka = 0.06 and 0.003 × 103 M−1 for fructose and xylose, respectively. Thus, covalent imprinting within the cross-linked micelles must have positioned the boronic acids quite accurately to match the hydroxyls on the templating sugar. Our MINPs were prepared with a 1:1 surfactant/DVB ratio. This amount of DVB was the maximum that could be solubilized by the micelle and corresponds to ~50 molecules of DVB per micelle. The high cross-linking density was found previously to be critical to the MINP binding selectivity.28

To our delight, the binding selectivity was reproduced when mannose and galactose were used as the templates. MINP(mannose), for example, bound its sugar template with Ka of 0.94 × 103 M−1 and no other d-aldohexoses except altrose (Ka = 0.56 × 103 M−1) (Table 1, entries 13–20; see Chart 1 for structures). MINP(galactose), likewise, only bound its template (Ka = 1.41 × 103 M−1) and one other sugar (gulose, Ka = 0.80 × 103 M−1) among the d-aldohexoses (Table 1S).

Molecular imprinting has become a very powerful technique to create guest-complimentary materials.32-43 Conventional typical MIPs, however, are intractable highly cross-linked polymers. In our case, because polymerization and cross-linking largely occurred within the boundary of the micelles, the MINPs were completely soluble in water due to their nanosize and hydrophobic/hydrophilic core–shell structure.28-31 Note that most MINPs in Table 1 had a single binding site per nanoparticle on average.44 The number of binding site per nanoparticle is controlled by the surfactant/template ratio used in the MINP preparation and, as demonstrated earlier, is fully tunable if desired.28 This number was determined by the ITC titration from the guest/host ratio.45 Previously, the ITC-determined binding stoichiometry was found to agree well with those determined by the Job plots for fluorescently labeled substrates.46

It is very interesting that a consistent binding selectivity was displayed by all three MINPs. Strong binding for the template sugar was fully expected. Why did the MINP bind only one of the remaining d-aldohexoses? The answer becomes clear when the following trends are considered.

(a) Inversion of two (or more) hydroxyl groups of the templating sugar turns off the binding essentially completely. This trend was seen from glucose to any of the diaxial sugars, and from mannose to allose/galactose/idose. The anomeric hydroxyl at C1 was not considered because it exchanges between the α and β form as the hemiacetal.

(b) The effect of a single hydroxyl inversion depends on the position of the hydroxyl. Consistently for all three MINPs, inversion at either C2 or C4 turned off the binding—e.g., from glucose to mannose/galactose or from mannose to glucose/talose. Inversion at C3, however, weakened the binding by 40–60%, e.g., from glucose to allose, mannose to altrose, or galactose to gulose. As shown by xylose, missing the C6 hydroxyl also caused a complete loss of binding.

When monoboronic acids bind free monosaccharides, literature generally agrees that binding of the first boronic acid occurs through the C1,2 hydroxyls of the sugar.4,47,48 Binding of the second boronic acid, however, could differ depending on the reaction conditions (e.g., aqueous or nonaqueous solvent, solution pH, concentration) and the structure of the boronic acid. The situation is complicated further by pyranose–furanose interconversion. Furanose, having the preferred synperiplanar 1,2-diols for boronate formation,17 is generally the minor component, sometimes representing <1% of the mixture. Nonetheless, two or all three of the C3,5,6 hydroxyls are frequently involved in the second boronate formation for furanose.4 There is also evidence that, for certain sugars, additional conformations (e.g., twist boat) may play roles in the binding, at least in aqueous alkaline media.48

In our case, the hydroxyls at C2, C4, and C6 were critical to the binding and the C3 hydroxyl played a secondary role. The results suggest that, under our conditions, the boronic acids probably bound two pairs of hydroxyls, at C1,2 and C4,6, respectively. Because the boronate template was synthesized in organic solvent under azeotropic distillation, neutral trivalent boronate esters instead of negatively charged tetravalent structures are expected.4

Solution pH has a large effect on the binding of small-molecule boronic acids. A change of pH from 6.5 to 8.5 increased the binding constant between phenyl boronic acid and glucose by over an order of magnitude.49 The pH effect came from the acid–based equilibria involved in the binding and the tetrahedral vs. trigonal forms of boronic acid/boronate. In our case, the same pH change barely had any effect on the MINP binding (compare entries 1, 11, and 12 of Table 1). Presumably, the overall hydrophobicity of the diboronate template means that the boronic acids would reside in a relatively hydrophobic region of the MINP. With poor solvent exposure, neither the boronic acids nor the boronate esters formed after binding would be very sensitive to the solution pH.

4-Nitrophenyl α-d-mannopyranoside 5 should interact with the MINP receptor through hydrophobic interactions, in addition to two boronate esters through the C2,3 and C5,6 hydroxyls.25 After template removal, a binding site is expected to form in the hydrophobic core of the cross-linked micelle, complementary to the 4-nitrophenyl group in size and shape. The hydrophobic imprinting worked very well for many substrates in our previous work.28-31 Consistent with the added hydrophobic interactions, binding between 5 and MINP(5) was over twenty times stronger than those between the sugars and their MINPs (Table 1, entry 21). Encouragingly, significant selectivity was found for the binding of similar glycosides. Glucopyranoside 6 was bound by MINP(5) with <1/3 of the binding affinity and mannopyranoside 7 with ~1/6. Apparently, inversion of one or two hydroxyl groups could still be easily distinguished, even for the pyranosides. Lastly, MINP(5) was also able to bind mannose with Ka = 0.5 × 103 M−1 (entry 24). The binding constant was similar to that between mannose and its own MINP (entry 14). Thus, the binding site imprinted from the mannopyranoside was able to bind mannose, most likely in the pyranose form.

The most significant discovery of this research is the general applicability of the MINP receptors, which are completely water-soluble and similar to proteins in size. It is very important that the MINP receptors displayed a very clear and consistent trend in the binding, mainly controlled by the C2, C4, and C6 hydroxyls of the d-aldohexoses. The milli- and submillimolar binding affinities already approached those found in natural lectins for monosaccharides. The observed binding selectivity suggests that the cross-linked micelles can be used as a platform to precisely position and orient binding groups even to distinguish minute structural changes in carbohydrates. If the same holds true for oligo- and polysaccharides, a general method for selective binding of carbohydrates will become available.

Answer: Molecular imprinting within cross-linked micelles using 4-vinylphenylboronate derivatives of carbohydrates provided water-soluble nanoparticle receptors selective for the carbohydrate templates. Complete differentiation of d-aldohexoses could be achieved by these receptors if a single inversion of hydroxyl occurred at C2 or C4 of the sugar or if two or more inversions took place. Glycosides with a hydrophobic aglycan displayed stronger binding due to increased hydrophobic interactions.


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:
based on recent basic and clinical studies , it has been shown that adipocytokines may contribute to the induction of carcinogens and progression of tumors ( 1 ) .

visfatin was initially recognized as a growth factor for proliferation of b - cell lymphocyte , called the pre - b cell colony - enhancing factor .
subsequently , it was found as a cytokine present in a variety of cells and tissues with metabolic and inflammatory effect .
visfatin have also been shown to correlate with pro - inflammatory cytokines such as il-1 , il-6 , and tnf . it stimulates il-6 and il-8 and may be associated with oxidative stress parameters .
modulation of insulin by binding to the insulin receptor is another recognized function for visfatin ( 2,3 ) .

previously , we reported the levels of various adipocytokines in patients with colorectal cancer and we found a significant increase in the visfatin serum level in colorectal cancer patients comparing to controls ( 4 ) .
therefore , we examined if this cytokine increases in patients with colorectal adenoma as a precursor of colorectal cancer .
to the best of our knowledge , in addition to a previous study done by nakajima et al .
( 1 ) , the present study is among the first reports to evaluate the visfatin level in patients with colorectal adenoma comparing to healthy controls .

 this case - control study was conducted at the department of surgery of imam medical complex affiliated to tehran university of medical sciences . between january 2014 and june 2015
, a total of 34 patients diagnosed with colorectal adenoma and 35 disease - free controls were included in case and control groups , respectively .
patients with a previous history of any colorectal disease including polyps , adenoma , irritable bowel disease or cancerous lesion were excluded from the study .
disease - free controls were selected from participants in the persian gulf healthy heart study ( 5 ) .
this study was carried out between march 2013 and march 2015 in colorectal surgery department of tehran university of medical sciences .
all the patients were informed about the study and written informed consent was taken from each patient .

 for each patient , systolic and
body mass index ( bmi ) and waist - to - hip ratio ( whr ) were calculated after measuring height , weight , waist circumference ( midway level between the costal margins and the iliac crests ) and hip circumference ( at the level of the greater trochanters ) . in order to measure serum markers ,
fasting venous blood samples were obtained from all patients and the disease - free controls .
serum biochemical parameters including blood glucose , triglyceride , and cholesterol levels were measured on the day of sampling using selectra 2 autoanalyzer ( vital scientific , spankeren , netherlands ) .
serum cholesterol ( hdl and total ) and triglyceride levels were measured using cholesterol oxidase / phenol aminoantipyrine and glycerol-3-phosphate oxidase phenol aminoantipyrine enzymatic methods , respectively . in cases with triglycerides level of less than 400 mg / dl , serum ldl was calculated using the friedewald formula .
enzyme - linked immunosorbent assay kits ( adipogen , seoul , korea ) were utilized in order to measure visfatin levels .
the assay sensitivity for visfatin was 0.10 ng / ml ; the intra- and inter - assay coefficients of variance were 3.85.5% and 6.49.5% , respectively .

descriptive values were expressed as the mean  sd . in order to compare visfatin levels between groups a two - tailed t - test was considered .
pearson s correlation was also used to assess the relationship between visfatin levels and other measured variables .

 this case - control study was conducted at the department of surgery of imam medical complex affiliated to tehran university of medical sciences . between january 2014 and june 2015
, a total of 34 patients diagnosed with colorectal adenoma and 35 disease - free controls were included in case and control groups , respectively .
patients with a previous history of any colorectal disease including polyps , adenoma , irritable bowel disease or cancerous lesion were excluded from the study .
disease - free controls were selected from participants in the persian gulf healthy heart study ( 5 ) .
this study was carried out between march 2013 and march 2015 in colorectal surgery department of tehran university of medical sciences .
all the patients were informed about the study and written informed consent was taken from each patient .

 for each patient , systolic and
body mass index ( bmi ) and waist - to - hip ratio ( whr ) were calculated after measuring height , weight , waist circumference ( midway level between the costal margins and the iliac crests ) and hip circumference ( at the level of the greater trochanters ) . in order to measure serum markers ,
fasting venous blood samples were obtained from all patients and the disease - free controls .
serum biochemical parameters including blood glucose , triglyceride , and cholesterol levels were measured on the day of sampling using selectra 2 autoanalyzer ( vital scientific , spankeren , netherlands ) .
serum cholesterol ( hdl and total ) and triglyceride levels were measured using cholesterol oxidase / phenol aminoantipyrine and glycerol-3-phosphate oxidase phenol aminoantipyrine enzymatic methods , respectively . in cases with triglycerides level of less than 400 mg / dl , serum ldl was calculated using the friedewald formula .
enzyme - linked immunosorbent assay kits ( adipogen , seoul , korea ) were utilized in order to measure visfatin levels .
the assay sensitivity for visfatin was 0.10 ng / ml ; the intra- and inter - assay coefficients of variance were 3.85.5% and 6.49.5% , respectively .

descriptive values were expressed as the mean  sd . in order to compare visfatin levels between groups a two - tailed t - test was considered .
pearson s correlation was also used to assess the relationship between visfatin levels and other measured variables .

 in this study a total of 69 cases including 34 patients with colorectal adenoma and 35 disease - free controls were enrolled .
patients included 18 males ( 53% ) and 16 females ( 47% ) and controls were 18 male ( 51% ) and 17 female ( 49% ) . patients and controls were also matched regarding their age as well .
demographic information of both groups and other studied variables including systolic and diastolic blood pressures , body mass index ( bmi ) , waist to hip ratio and lipid profile of patients have been summarized in table 1 . as can be seen in table 1
, there was no significant statistical difference among the patients and the controls in terms of these variables ( p>0.05 in all comparisons ) .

* p < 0.05 were considered significant .

 * * two - tailed t - test was used to compare visfatin levels between groups .
pearson s correlation was used to evaluate the relationship between visfatin levels and other measured variables .

meansd of visfatin levels in male and female patients were 6.33.01ng / ml and 7.13.05ng / ml , respectively . the visfatin level in the control group was 7.22.41ng / ml and 6.42.59ng / ml for males and females , respectively
. moreover , there was no significant difference in terms of the visfatin level between both gender in each group ( p=0.482 for patients and p=0.375 for controls ) .
we also tried to analyze any possible correlation between the visfatin levels and each of the mentioned studied variables . except for a significant correlation between the bmi value and visfatin level ( p=0.041 ) ,
visfatin levels were analyzed separately based on the location of the adenoma within the large intestine in the patient group ( table 2 ) .
we found no significant difference between the levels of visfatin in each location comparing the healthy controls ( p>0.05 in all comparisons ) .
there was no statistical difference between the locations groups in terms of visfatin level as well ( p=0.068 ) .

* values show possible differences between visfatin levels of patients suffering from adenoma in each part of colon or rectum comparing to the control levels .

 visfatin can be found in significant amounts in adipose tissue and it is produced primarily by visceral adipose tissue .
therefore , visfatin serum levels may be affected by a change in body weight and relationship between obesity , bmi and serum levels of visfatin has also been documented ( 2,6 ) .
although the visfatin level had a significant relation with the bmi value in our adenoma patients , we found no statistical significant relation in the healthy controls .

metabolic syndrome is a group of harmful metabolic abnormalities , including visceral obesity , hyperglycemia , dyslipidemia , and hypertension .
increased circulating visfatin levels have also been found in patients with metabolic syndrome ( 7,8 ) .
therefore , we tried to depict any relation between visfatin level and metabolic abnormalities involved in metabolic syndrome in patients with colorectal adenoma .
although we found a significant relation between the visfatin level and bmi of patients , we did not detect any relation for hyperglycemia , hypertension ( systolic and diastolic ) and dyslipidemia ( hyper cholesterolemia or hypertriglyceridemia ) .

sigmoid ( 13 patients , 38.2% ) and rectum ( 13 patients , 38.2% ) were the most common site followed by ascending colon ( 6 patients , 17.6% ) . ascending ( 3.923.25 ng / ml ) and transverse colon ( 8.551.34 ng / ml ) had the lowest and highest mean serum levels of visfatin , respectively .
nevertheless , our analysis revealed no significant difference between these levels and the value for the visfatin level in normal controls .
nakajima et al . ( 1 ) analyzed the possible relations between the size and number of colorectal adenomas and some adipocytokines including the visfatin .
they found that except for adiponection , other cytokines including the visfatin has no relation with these two factors .
consequently , according to this study and our findings , it seems that size , number and location of colorectal adenoma are not influential factors affects the adipocytokine levels .

low number of cases was the major limitation in our study . designing another study with higher number of patients

 although visfatin level has been shown to be increased in serums of patients with colorectal cancer , it does not significantly increase in cases with colorectal adenoma .
site of adenoma within the colon or rectum does not seem to play an important role in this regard as well .

Answer:
background : visfatin is an adipocytokine secreted by visceral adipose tissue . it has been shown
 that adipocytokines may contribute to the induction of carcinogens and progression of tumors . previously ,
 we found a significant increase in the visfatin serum level in colorectal cancer patients .
 herein ,
 we investigated if this cytokine increases in patients with colorectal adenoma as a precursor of
 colorectal cancer .

 methods : in this case - control analytic study , a total of 34 patients diagnosed with colorectal adenoma
 and 35 disease - free controls were included .
 adenomas were also categorized based on their
 location within the colon .
 visfatin serum levels were measured in all cases and controls using enzyme-
 linked immunosorbent assay kits . in order to compare visfatin levels between groups a twotailed
 t - test was considered .
 pearson correlation was also used to assess the relationship between
 visfatin levels and other measured variables .

 results : patients included 18 male ( 53% ) and 16 female ( 47% ) with a meansd age of 48.310.96
 years and controls were 18 male ( 51% ) and 17 female ( 49% ) with a meansd age of 51.612.52
 years . there were no significant difference in terms of the visfatin level between the two groups
 ( 6.73.01 ng / ml for patients and 6.82.49 ng / ml for controls , p>0.05 ) . except for a significant correlation
 between the bmi and visfatin level ( p=0.041 ) , no other correlation was detected .
 we found no
 significant difference between the levels of visfatin in each location of adenoma comparing the
 healthy controls ( p>0.05 in all comparisons ) .
 there was no statistical difference between the locations
 groups in terms of visfatin level as well ( p>0.05 ) .

 conclusion : visfatin serum level does not significantly increase in patients with colorectal adenoma .
 site of adenoma within the colon or rectum does not seem to play an important role in this regard
 as well .


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:
an 81-year - old female with oavs presented to a general dentist for a dental implant consultation .
her medical history was remarkable for an epibulbar dermoid and previous grafting of an anterior mandibular defect at the age of 16 .
after a routine examination , the patient was referred to an oral and maxillofacial surgeon for implant treatment planning .
the surgeon requested a maxillofacial cbct scan extending from the level of the nasal fossa through the inferior border of the mandible , and from the anterior border of one ramus to the anterior border of the contralateral ramus . upon radiographic examination ,
the bilateral paramedian area of the mandible appeared abnormally heterogeneous with a poorly defined border on the right .
the mandibular canals anterior to the right second molar and the left mental foramen were untraceable ( fig .
1 ) . multiplanar reconstructions revealed a large , heterogeneous , expansile entity of mixed density along the facial side of the mandible , extending from the mandibular left premolar area to the mesial aspect of the mandibular right third molar , and from the level of the root apices through the inferior border of the mandible .
effacement of the facial cortical plate without an effect on the neighboring teeth was observed ( fig .
3 ) . three - dimensional volume rendering depicted the considerable size of the entity in question ( fig .
4 ) . a cartilaginous neoplasm could not be ruled out based on cbct imaging and an incisional osseous biopsy was therefore performed .
hematoxylin and eosin - stained slides prepared after formalin fixation and decalcification were reviewed ( fig .
growth or overgrowth is a recognized sequela of ccgs . almost all patients that seek corrective surgery following ccg overgrowth in the mandibular body or condyle present with facial asymmetry .
this happens even when the grafts are placed bilaterally due to their unpredictable growth potential . for a definitive diagnosis to be made , radiographic examination followed by a histopathological evaluation is indicated.9 most of the published cases of ccg overgrowth in the mandible were described radiographically using panoramic images and/or multi - detector computed tomography ( mdct).10111415161718 yang et al.9 reviewed 68 cases of ccg overgrowth in the maxillofacial region .
the authors described a case of overgrowth of a ccg that replaced the right mandibular body using panoramic , lateral cephalometric , and posteroanterior skull radiographs , and mdct .
none of the radiographs demonstrated asymmetry due to the inherent limitations of this imaging modality .
mdct allowed better visualization of the facial deformity and chin deviation in all dimensions.9 the advantage of the 3-dimensional visualization of such complex cases using mdct is indisputable .
however , plain radiography is still commonly used due to its availability , low cost , and reduced patient exposure to ionizing radiation .
the authors reported 4 cases that demonstrated low - attenuation grafts with occasional foci of high attenuation , clear borders between the graft and host bone , and lateral and superior rims of ossification using mdct .
the follow - up period of these cases ranged from 5 months to 8 years .
a clear border was only seen in the case in which only 5 months had elapsed since surgery .
fukuta et al.16 published a case of recurrent overgrowth of a ccg placed for hemimandibular reconstruction using panoramic images , mdct , and a nuclear medicine bone scan .
these images were of poor quality , but the authors noted the deviation of the mandible on mdct on 2 occasions ( before each corrective operation ) and increased uptake of the radionuclide by the graft on the third day after surgery .
this profound growth potential may have been due to the patient 's young age ( 2 years old ) .
similarly , samman et al.18 demonstrated an increase in isotope uptake by the graft using technetium scintigraphy , supporting the theory that ccgs have an inherent growth potential .
kaban et al.11 described the incorporation and calcification of a ccg replacing the mandibular condyle , and ultimately resembling a normal condyle upon periodic follow - up .
unfortunately , the quality of the images was poor in the previous articles , which made us unable to evaluate the imaging findings .
eckardt et al.10 described a case of ccg reconstruction after hemimandibulectomy in which follow - up was performed at regular intervals , up to 6 years after surgery , using panoramic images .
the authors used linear and angular measurements to calculate the ratio between the operated and unoperated side to evaluate overgrowth versus growth retardation .
although this approach is inaccurate , as panoramic images are prone to positioning errors and unpredictable distortion between successive images and within the same image;19 significant growth of the ccg along the vertical dimension was evident .
ko et al.13 accurately used landmarks on lateral and posteroanterior cephalometric radiographs to assess ccg growth .
the authors noted that the follow - up period was critical when evaluating overgrowth ; the longer the follow - up period , the more growth they found in their sample .
jang et al.20 described the case of a ccg extending from the angle of the mandible and replacing the condyle using ct .
the graft appeared stable with no signs of resorption or overgrowth at 10 months after surgery .
schatz and ginat8 pointed out that autografts have the disadvantage of resorption hindering their cosmetic effect .
the authors demonstrated a low - attenuation cartilage graft with a peripheral rim of ossification using an axial mdct image .
karacaolan et al.21 also demonstrated that cartilage grafts had a tendency to undergo resorption , using magnetic resonance imaging ( mri ) after a 12-month follow - up period to assess the degree of resorption .
the majority of the grafts had a low signal with a few foci of high signal near the soft tissue periphery on follow - up imaging .
no article in the literature described similar growth or changes in synthetic cosmetic implants in the soft tissue .
however ; cosmetic implants , like autogenous grafts , can become incorporated into the underlying bone .
other complications associated with cosmetic implants include migration , extrusion , erosion , and foreign bone reaction.8 with the increased use of radiographic imaging to diagnose and treat a variety of dental and medical conditions , there is an increased likelihood of incidental findings , such as implants that were not expected based on the patient 's history .
a history of implants for cosmetic purposes may not be elicited because the patient may not feel that they are important to the issue being discussed .
although most implants and grafts will present as benign - looking entities within the soft tissue that can easily be interpreted as such , some may present as unusual entities that may mimic a more serious disease , such as a benign or malignant neoplasm .
the common management of facial defects in oavs includes reconstructive surgery , often using implants or grafts to improve patients ' cosmetic appearance .
we present the case of an incidentally found cosmetic graft . according to the patient ,
an autogenous rib graft was harvested and sectioned to augment the mandibular symphysis . on imaging ,
attempts to recover previous medical and surgical notes were unsuccessful , as the surgeon who performed the procedure in 1950 was deceased .
the exact surgical technique used was unclear ; however , the graft had maintained its proper anatomical location and aesthetic shape for over 65 years .
the most probable surgical technique may have involved the surgeon dicing the osteocartilage into multiple pieces and creating a tunnel between the mandibular periosteum and overlying mucosa to hold the diced cartilage graft in place during the healing period.21 to our knowledge , this is the last published case of an anterior mandibular costochondral graft . no case with long - term follow - up
has been published and a review of the literature concerning imaging related to cosmetic facial grafts did not identify any similar cases .
clinical correlations , imaging , and histology were essential to render a final diagnosis of costochondral graft material .
the histopathology suggested a benign cartilaginous process ; however , the anterior mandible is a rare site for benign cartilaginous neoplasms , and without proper clinical and radiographic correlations the lesion could have been misdiagnosed .
however , mandibular osteochondromas have almost exclusively been reported in the condyle.22 the characteristic imaging findings of an osteochondroma , involving a pedunculated or sessile bony cortical mass continuous with the underlying bone , were absent .
facial implants and grafts are found incidentally in many cbct studies performed for dental treatment .
a thorough knowledge of their normal appearance is important in order to recognize what is abnormal .
based on imaging alone , chondrosarcoma was initially considered due to the speckled diffuse flocculent calcification and the infiltration into adjacent normal bone .
chondrosarcomas occur where cartilaginous tissues may be present and may occasionally occur in the symphyseal region.23 schatz and ginat8 discussed the imaging appearance of these augmentation materials using ct and mri .
chin augmentation materials such as hydroxyapatite , silicone implants , and cartilage grafts have been described .
the authors concluded that cartilage grafts appear to have a soft tissue density that  may form a rim of calcification or ossification.8 our case involved a more diffuse calcification pattern , which may have been due to the longer follow - up period .
although most are well defined and radiographically homogeneous , being of relatively inert non - biological material , immune reactions to some may stimulate alterations in the appearance of surrounding tissues .
biological implants may undergo growth and differentiation , causing their appearance to mimic neoplastic lesions .
we present the case of a costochondral graft in the soft tissue anterior and facial to the mandible , with changes mimicking a cartilaginous neoplasm . in light of the fact that chondrosarcomas are known to occur in the anterior rib cage , an evaluation of random growth
a vascularized graft is thought to be more controlled in growth than a nonvascularized graft .
this is the first case to report the cbct imaging features of a long - standing graft in the anterior mandible .

Answer:
to our knowledge , the imaging features of costochondral grafts ( ccgs ) on cone - beam computed tomography ( cbct ) have not been documented in the literature .
 we present the case of a ccg in the facial soft tissue to the anterior mandible , with changes mimicking a cartilaginous neoplasm .
 this is the first report to describe the cbct imaging features of a long - standing graft in the anterior mandible .
 implants or grafts may be incidental findings on radiographic images made for unrelated purposes .
 although most are well - defined and radiographically homogeneous , being of relatively inert non - biological material , immune reactions to some grafts may stimulate alterations in the appearance of surrounding tissues .
 biological implants may undergo growth and differentiation , causing their appearance to mimic neoplastic lesions .
 we present the case of a cosmetic autogenous ccg that posed a diagnostic challenge both radiographically and histopathologically .


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:
Various types of non-covalent interactions contributing towards crystal packing of halogenated diphospha-dicarbaborane with an open pentagonal belt

Paper sections:

Innerly and/or outerly substituted boron cluster hydrides (heteroboranes) of various architectures are known for various types of non-covalent intermolecular interactions and thus serve as good models for the evaluation and mutual comparison of various types of hydrogen, dihydrogen (diH), halogen (X), chalcogen, pnictogen (Pn) or even tetrel bonds. 1,2 The neutral nido-B 7 P 2 [C(R)] 2 H 7 cage with an open P 2 CBC pentagonal belt can be formally obtained from nido-B 11 H 11 4À (nido-B 11 H 14 À exists) 3 by replacing four BH vertices with two tetrel and Pn vertices. Miscellaneous dicarba dipnictogen nido eleven-vertex heteroboranes have been prepared by reacting arachno-4,5-C 2 B 7 H 13 with PCl 3 , AsCl 3 and SbCl 3 . [4][5][6] The crystal structures of 3-Cl-nido-7,8, (3) compounds are already known. [4][5][6] The crystal packing of 3 is governed by Pn-bonds. 6 In contrast to 3, it has not been possible to record the singlecrystal X-ray data of the parent nido-7,8,9,11-P 2 C 2 B 7 H 9 and nido-7,8,9,11-As 2 C 2 B 7 H 9 in sufficient quality. Interestingly, it is feasible to determine the structure of single-crystal halogenated compounds 1 and 2, revealing a supramolecular architecture mainly resulting from extensive Pn-bonding. [4][5][6] In order to proceed in the examination of the non-covalent interactions of nido-heteroboranes, we attempted to iodinate 1 (Fig. 1) by the reaction with elemental iodine in the presence of aluminum trichloride (details in ESI †). The resulting 3-Cl-10-I-nido-7,8,9,11-P 2 C 2 B 7 H 7 (4) was obtained in a moderate yield of 49% and was characterized in solution in terms of multinuclear NMR spectroscopy (Table 1).

In the crystal structure of 4 (Fig. 2), four molecules have been found in the unit cell. The structure of the cage of 4 is essentially the same as found for 1 4 except for the very slight shortening of the B(10)-C(9/11) bonds inside the open P 2 CBC pentagonal belt caused by the substitution of the B(10) atom by the heavy iodine. In fact, there are only two examples of a similar structural pattern in the Cambridge Structural Database, i.e. dicarba-closo-dodecaborane-1,2-diyl-1,2-bis(diisopropylamino)diphosphines, 9 but these are heavily distorted with no option of a serious structural comparison.  The discrepancy between the calculated and experimental chemical shift results from the neglect of the effect of spin-orbit (SO) coupling on the overall shielding, which is not taken into account in the GIAO-MP2 scheme. However, it has been shown that due to iodine being terminally bonded to a boron atom within a neutral boron cluster, SO coupling increases the contribution of this B atom towards overall shielding by about 20 ppm, 7,8 which would considerably improve the fit in the present case.

a Institute of Inorganic Chemistry of the Czech Academy of Sciences,

To better understand non-covalent interactions of 4, we computed its ESP potential (Fig. 3) and compared it with other recently studied analogous compounds, 1-3. Compound 1 has only one highly positive s-hole located on the P vertices. The other expected s-holes of 1 could not be defined on the P vertices due to the more positive neighboring CH vertices. The Sb and As vertices of 2 and 3 have more positive ESP surfaces than the CH vertices. Both molecules thus have three well-defined s-holes on the Pn atoms. From this point of view, the ESP surface of 4 is thus analogous to 2 and 3. Compound 4 has three s-holes located on P atoms with the same magnitude (V S,max ) of 31.5 kcal mol À1 . The P vertices of 4 have even more positive ESP values than the CH vertices. The ESP surface on top of the CH vertices has the value of 28.2 kcal mol À1 . Besides the s-holes located on P atoms, the 4 compound also has s-holes on the X atoms. While the I atom has a positive s-hole with the V S,max value of 6.8 kcal mol À1 , the Cl atom only has a relative s-hole (i.e. the top of the Cl atom is less negative than its belt but the V S,max value is negative). The 4 compound can thus form Pn-, H-and X-bonds, the last of which are, however, less probable due to the lower V S,max values on the X atoms (Table 2). The most negative ESP surface of 4 is on the negative belt on the I and Cl atoms (the magnitudes of À15.1 and À12.3 kcal mol À1 , respectively).

Finally, we have studied pairwise interactions in the crystal structure of 4 and compared them with those of 1, 2 and Highly-accurate MP2/CBS interaction energy (DE) values are summarized in Table 3 (see also Fig. 4). The AÁ Á ÁB motif is the most stable motif of 4. The motif can be described as two symmetrical P 2 Á Á ÁI Pn-bonds. Since the Pn-bond is quite long (3.8 Å), it could also be seen as a nonspecific dispersion contact with an optimal dipole-dipole arrangement. The DE value of À9.5 kcal mol À1 is very large, considerably more negative than the most negative bonding motifs of 1 and 2 (the DE of about À6.0 kcal mol À1 ), which also had two Pn-bonds. However, considering that the AÁ Á ÁB motif of 4 has two Pn-bonds, they are weaker than the Pn-bonds of 3. Compound 3 has a binding motif that is exclusively formed by a single Pn-bond and has the DE value of À6.5 kcal mol À1 . 6 The AÁ Á ÁC motif, formed by two symmetrical C-HÁ Á ÁI-B H-bonds, has DE of À6.5 kcal mol À1 . The H-bond is again rather long (3.2 Å). The third most stable motif is AÁ Á ÁD with DE of À6.1 kcal mol À1 . It is formed by the C-HÁ Á ÁH-B dihydrogen bond and the C-HÁ Á ÁI-B H-bond. The C-HÁ Á ÁH-B diH-bond is the only contact in the crystal structure of 4 with the length below the sum of van der Waals radii (2.9 Å between the H and Fig. 2 The molecular structure (ORTEP 50% probability level) and atomic numbering of 4. The selected interatomic distances [Å] are: I1-B10 2.184(2), Cl1-B3 1.786(2), B2-C11 1.730(3), B2-P7 2.053(2), B3-P8 2.1117(19), B3-P7 2.113(2), B4-C9 1.732(2), B4-P8 2.0516(18), B5-C9 1.715(3), B6-C11 1.715(2), C9-B10 1.608(2), C9-P8 1.8681(17), C9-H9 0.91(3), B10-C11 1.604(3), C11-P7 1.8706(19) and P8-P7 2.1970 (6). For all the distances and other structural characteristics, see Table S2 (ESI †).   the center of the B-H bond; HÁ Á ÁH and HÁ Á ÁB distances of 2.3 and 3.0 Å, respectively). The AÁ Á ÁE motif also has all contacts much higher than the sum of the van der Waals radii (e.g. the P 2 Á Á ÁCl Pn bond of 3.9 Å). In summary, compound 4 (3-Cl-10-I-nido-7,8,9,11-P 2 C 2 B 7 H 7 ) was prepared by reacting 3-Cl-nido-7,8,9,11-P 2 C 2 B 7 H 8 with elemental iodine in the presence of aluminum trichloride. Its molecular structure has been characterized by NMR spectroscopy, X-ray crystallography and ab initio computations. Apart from B (10) there is a good accord between the experimental and computed 11 B chemical shifts. It is the spin-orbit coupling that is responsible for such a disagreement related to B (10). The combination of Pn-, diH and H-bonds turned out to be a driving force for the crystal packing as revealed by quantum chemical computations.

Conflicts of interest

There are no conflicts to declare. Fig. 4 The most significant interaction motifs from the crystal structure of 3-Cl-10-I-nido-7,8,9,11-P 2 C 2 B 7 H 7 (4). The distances are in Å. The positions of the H atoms have been optimized at the DFT-D3/BLYP/DZVP level. 10

Answer: Various types of non-covalent interactions contributing towards crystal packing of halogenated diphospha-dicarbaborane with an open pentagonal belt † Josef Holub, a Zden ˇka Ru ˚z ˇic ˇkova ´,b Pavel Hobza, * c Jindr ˇich Fanfrlı ´k, * c Drahomı ´r Hnyk * a and Ales ˇRu ˚z ˇic ˇka* bWe have prepared 3-Cl-10-I-nido-7,8,9,11-P 2 C 2 B 7 H 7 by the reaction of 3-Cl-nido-7,8,9,11-P 2 C 2 B 7 H 8 with I 2 in the presence of AlCl 3 .The product was obtained in a yield of 49% and was characterized by NMR spectroscopy and X-ray crystallography. Quantum chemical calculations have demonstrated that the crystal structure is stabilized by hydrogen, dihydrogen and pnictogen bonds.


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:
it is well established that the presence of neoplasms in the upper tract urothelium necessitates the en bloc removal of the ipsilateral kidney , ureter , and bladder cuff as the standard of care based on the premise that urothelial cancers are caused by a field change or defect . however , due to the morbidity associated with open nephroureterectomies , conservative management may be appropriate for poor surgical candidates .
percutaneous and ureteroscopic techniques have been utilized in the management of urothelial tumors with percutaneous access required to treat larger of upper tract urothelial cancers being used in suitable candidates.various techniques for this approach have been reported including monopolar electrocautery , laser , rollerball , and electrovaporization .
the reported recurrence rates have been low , and disease - free survival is comparable to that in patients treated with nephroureterectomy . the use of monopolar electrosurgery however can interfere with cardiac pacemakers resulting in potentially fatal dysrhythmias .
we report the case of an upper tract urothelial carcinoma in the renal pelvis resected with bipolar cautery through percutaneous access without deactivation of the cardiac pacemaker . to our knowledge
an 82-year - old man who was a lifelong nonsmoker presented with a history of intermittent gross hematuria .
his medical comorbidities included non - insulin - dependent diabetes , hypertension , hypercholesterolemia , hypothyroidism , chronic renal insufficiency ( creatinine 2.4 mg/ dl ) , multiple transient ischemic attacks , stroke , sleep apnea , peripheral vascular disease resulting in a below - knee amputation , colon resection for diverticulitis , and a vdd pacemaker ( model # 640 , vitatron , minneapolis , mn ) for bradycardia .
his preoperative cardiac risk was goldman class ii - iii , and he was at high risk of developing a deep venous thrombosis .
the retrograde pyelogram on the right side was normal , but the left retrograde pyelogram demonstrated moderate hydronephrosis in a bifid collecting system and a 2-cm filling defect in the renal pelvis with renal malrotation ( figure 1 ) .
a ct scan of the abdomen and pelvis revealed a tumor limited to the left renal collecting system with no evidence of metastases .
retrograde pyelogram displaying a renal filling defect in a bifid renal collecting system with a malrotated kidney .
based on a background of renal insufficiency , the options were discussed with the patient and a tumor ablation with the holmium : yag laser and flexible ureteroscopy was carried out .
the ureteroscopic procedure was ineffective in completely ablating the tumor at its stalk because the ureteroscope could not fully access the tumor due to the capacious renal pelvis and renal malrotation .
this patient was dependent on his vdd pacemaker , thus making monopolar cautery potentially hazardous .
therefore , a percutaneous resection using a bipolar resectoscope was planned under a second general anesthetic without deactivating the pacemaker .
with the patient under general anesthesia , percutaneous access to the kidney was obtained , the tract was dilated to 30 f , and an amplatz sheath was inserted .
a resectoscope using bipolar cautery ( vista , acmi corporation , south - borough , ma ) was used to resect the tumor ( settings : cut , 6 ; coagulation , 6 ) through the amplatz sheath .
the operation lasted 30 minutes without any evidence of dysrhythmias or interference with the pacemaker .
a 22 f nephrostomy tube was left indwelling until postoperative day 1 when it was removed , and the patient was discharged home without any complications .
the patient used a continuous positive airway pressure ( cpap ) machine postoperatively that helped prevent any postoperative respiratory complications .
the patient was seen in follow - up at 3 months with an intravenous pyelogram ( ivp ) that was free of any filling defects and negative cytology .
serum creatinine increased only slightly from 2.4 mg / dl ( preoperatively ) to 2.6 mg / dl , postoperatively . at 8 months
, a retrograde pyelogram revealed a recurrence of his upper tract tumor that was too large for ureteroscopic management , and percutaneous bipolar resection was once again undertaken .
the patient declined upper tract bacille calmette - gurin therapy and laparoscopic nephroureterectomy due to his declining health including a recent cerebral vascular accident . at 6 months ,
the patient remains free of recurrent or metastatic disease with stable renal function ( 2.5 mg / dl ) .
bipolar electrocautery was introduced over 20 years ago as an energy source for endourologic procedures .
the potential benefits of bipolar energy include the use of isotonic normal saline irrigation and improved hemostasis .
importantly , it can also be used on patients with permanent cardiac pacemakers and has been described in a case involving transurethral resection of a bladder tumor in a similar pacemaker - dependent patient .
electrocautery - induced cardiac pacemaker failure or malfunction has been well described.since the invention of cardiac pacemakers nearly 50 years ago , electromagnetic interference has been a concern for patients who wear them . over the years , despite improved technology , permanent cardiac pacemakers remain susceptible to this electromagnetic interference , including electrocautery , during surgical procedures . traditionally , the use of monopolar electrosurgery is avoided in patients with cardiac pacemakers because the monopolar current passes from the instrument tip through the patient 's body towards the ground plate and may adversely affect the pacemaker , resulting in potentially fatal dysrhythmias .
bipolar electro - surgery can reduce the level of interference between electrocautery units and pacemaker electrodes .

bipolar electrosurgery has also been shown to reduce the depth of thermal damage at the site of surgery . in an ex vivo
porcine kidney model , wendt - nordahl et al compared the effects of the vista bipolar system to monopolar cautery .
the depth of thermal damage was significantly deeper at 300 m measured with the monopolar resectoscope but only reached 160 m with the bipolar device even at the highest output level ( level 8) .
excessive heat may cause problems with the urothelium of the renal collecting system or penetrate deeply into parenchyma resulting in arteriovenous fistulae .
however , in patients with significant medical comorbidities who are not candidates for radical surgery , bipolar resection through a percutaneous access is an alternative .
given the patient 's cardiac status , a bipolar resectoscope was used not only to perform tumor resection but also to minimize the risk of electrical interference with the pacemaker .
both ureteroscopy and percutaneous laser ablation would have been tedious due to tumor size and location .
disease recurrence occurred due to multifocality and not due to failure of the initial bipolar procedure .
it can be argued that the patient underwent 2 endoscopic procedures while under general anesthesia , whereas a laparoscopic nephroureterectomy would have offered treatment in a single procedure ; however , the single procedure would have required more surgical time in one sitting and is much more invasive than 2 short endoscopic procedures . the mortality and morbidity risk would be higher with a nephroureterectomy than 2 shorter endoscopic procedures .
while the use of the bipolar electrocautery may be advantageous in the percutaneous resection of upper tract urothelial tumors , potential drawbacks of this technique include limited utility depending on tumor location and access , and dessication of the tissue creating more artifacts for pathological examination .
it is advisable to perform a cold biopsy of the tumor for both pathology and margin status before using the bipolar electrocautery .
more importantly , this approach is not a replacement for nephroureterectomy but may be an option for nonsurgical candidates or patients who may benefit from nephron - sparing procedures
. it may be a palliative procedure in some cases and potentially therapeutic in others . as illustrated in this case
, the use of bipolar electrocautery circumvents the potential risks of using electrocautery in patients with cardiac pacemakers .
bipolar electrocautery is a safe and feasible resection modality in percutaneously approached upper tract urothelial neoplasms in patients with cardiac pacemakers .

Answer:
percutaneous approaches to upper tract urothelial cancers have been performed in patients unsuitable for radical nephroureterectomy .
 we present the case of an 82-year - old man with significant comorbidities including dependency on a cardiac pacemaker . without deactivating the pacemaker , we used bipolar cautery to percutaneously resect a large upper tract urothelial tumor in the renal pelvis .
 bipolar cautery is a suitable method of percutaneous or transurethral resection in patients who are pacemaker dependent .


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:
between july 2010 and june 2013 , 385 csf cytology samples were collected from 42 patients with the presence of a metastatic tumor confirmed by at least two histologic or cytological studies .
cytology samples obtained before adjuvant therapies were excluded to evaluate the diagnostic rate of csf cytology more consistently .
the breakdown of the patient population was as follows : 25 males and 17 females , with a median age of 55 years ( range , 29 to 77 years ) .
the mean observation period was 5 months ( range , 1 to 22 months ) , and the mean number of csf examinations was 9 ( range , 2 to 34 ) .
all patients underwent an operation for the placement of a ventricular catheter and reservoir as well as consecutive csf collections using the reservoir ( fig .
to minimize dry artifacts and prevent cell degeneration , samples were delivered to the department of pathology immediately upon collection .
samples were then processed using liquid - based cytology ( lbc ) ( thinprep , cytyc co. , boxborough , ma , usa ) , an automated method of preparation and smearing of cells in a monolayer .
of the 385 csf samples , 54 were processed by a conventional smear method rather than the liquid - based method because those samples were obtained when the liquid - based method was not available for csf cytology .
immunocytochemistry ( icc ) was performed using a ventana xt automated stainer ( ventana co. , tucson , az , usa ) with an antibody to cytokeratin ( 1:300 , ae1/ae3 , dako , carpinteria , ca , usa ) .
slides were incubated with primary antibody for 32 minutes at 37 followed by a universal secondary antibody for 8 minutes at 37. slides were incubated in streptavidin - horseradish peroxidase d for 16 minutes at 37 , and then the substrate , 3,3'-diaminobenzidine tetrahydrochloride ( dab ) h2o2 , was added for 8 minutes , followed by hematoxylin and bluing reagent counterstains at 37. cases without atypical cells suggestive of metastasis were diagnosed as negative for malignancy .
a positive diagnosis of malignancy was defined as the presence of atypical cells with cytokeratin immunoreactivity , regardless of the amount ( fig .
2 ) . there were some cases that presented with atypical cells on papanicolaou - stained slides , but it was not possible to evaluate many of these cases using cytokeratin icc slides because the cells disappeared during the staining process . in those cases , we termed the diagnosis suspicious for malignancy , and these cases were regarded as positive findings when calculating the diagnostic rates .
all slides , including those for icc , were independently reviewed by two pathologists ( s.h.k and y.s.b ) .
between july 2010 and june 2013 , 385 csf cytology samples were collected from 42 patients with the presence of a metastatic tumor confirmed by at least two histologic or cytological studies .
cytology samples obtained before adjuvant therapies were excluded to evaluate the diagnostic rate of csf cytology more consistently .
the breakdown of the patient population was as follows : 25 males and 17 females , with a median age of 55 years ( range , 29 to 77 years ) .
the mean observation period was 5 months ( range , 1 to 22 months ) , and the mean number of csf examinations was 9 ( range , 2 to 34 ) .
all patients underwent an operation for the placement of a ventricular catheter and reservoir as well as consecutive csf collections using the reservoir ( fig .
to minimize dry artifacts and prevent cell degeneration , samples were delivered to the department of pathology immediately upon collection .
samples were then processed using liquid - based cytology ( lbc ) ( thinprep , cytyc co. , boxborough , ma , usa ) , an automated method of preparation and smearing of cells in a monolayer .
of the 385 csf samples , 54 were processed by a conventional smear method rather than the liquid - based method because those samples were obtained when the liquid - based method was not available for csf cytology .
immunocytochemistry ( icc ) was performed using a ventana xt automated stainer ( ventana co. , tucson , az , usa ) with an antibody to cytokeratin ( 1:300 , ae1/ae3 , dako , carpinteria , ca , usa ) .
slides were incubated with primary antibody for 32 minutes at 37 followed by a universal secondary antibody for 8 minutes at 37. slides were incubated in streptavidin - horseradish peroxidase d for 16 minutes at 37 , and then the substrate , 3,3'-diaminobenzidine tetrahydrochloride ( dab ) h2o2 , was added for 8 minutes , followed by hematoxylin and bluing reagent counterstains at 37.
cases without atypical cells suggestive of metastasis were diagnosed as negative for malignancy . a positive diagnosis of malignancy was defined as the presence of atypical cells with cytokeratin immunoreactivity , regardless of the amount ( fig .
2 ) . there were some cases that presented with atypical cells on papanicolaou - stained slides , but it was not possible to evaluate many of these cases using cytokeratin icc slides because the cells disappeared during the staining process . in those cases , we termed the diagnosis suspicious for malignancy , and these cases were regarded as positive findings when calculating the diagnostic rates .
all slides , including those for icc , were independently reviewed by two pathologists ( s.h.k and y.s.b ) .
lung was the most common primary site with 22 cases , followed by breast with 6 cases .
of the 385 specimens , 132 were diagnosed as positive for malignancy and 27 were suspicious for malignancy , for a total of 159 specimens considered to have a positive diagnosis of malignancy . among the 42 patients ,
3 were never diagnosed as malignant by cytology examination even though all were confirmed to have cns metastasis on brain tissue biopsy .
the positive malignancy diagnosis rates in the other 31 patients ranged from 4.5% to 87.5% , and the mean positive rate was 41.3% .
table 2 demonstrates two representative cases ( case nos . 4 and 12 ) from our series .
during a period of two months , these two patients underwent 13 and 15 csf cytology examinations , which yielded positive results in 6 and 10 of the tests , respectively .
the intervals between csf cytology examinations ranged from 0 to 13 days and were short enough to enable more meticulous analysis of consecutive diagnostic rates . however , the results appeared random , without a consistent trend . even within the same day ,
rapid transport is important for optimal cellular preservation in csf materials , which can be cytolysed quickly . in order to reduce the number of nondiagnostic cases ,
csf materials should be examined as soon as possible after collection . from a routine diagnostic viewpoint ,
degeneration is one of the most problematic artifacts when diagnosing cytology slides , as csf specimens tend to degenerate more readily than other cytology specimens .
we were able to control artificial factors by reminding clinicians of the importance of rapid processing and encouraging them to submit the samples immediately .
most previous studies concerning the diagnostic rates of csf examination used the lumbar puncture as a diagnosing modality.4 - 6 however , lumbar puncture can be harmful to patients and difficult for clinicians because it is an invasive procedure .
it is this for reason that most previous studies regarding the diagnostic accuracy of csf performed only one csf examination per patient . in this study , however , consecutive csf sampling was performed using the ventricular catheter and reservoir from each patient .
although a neurosurgical procedure is required to implant a ventricular catheter in patients , it enables the continuous collection of csf and consecutive analysis .
lbc is now a widely used method for preparing cytology samples and has achieved broad acceptance for most cytology specimens.8 - 11 furthermore , for the diagnosis of metastatic tumors in csf , thin - layer lbc has been suggested as an appropriate diagnostic method.12,13 as in immunohistochemistry , icc improves the diagnostic rates because cytology is often difficult and problematic to evaluate using cellular morphology alone.14 using lbc is more convenient for performing icc than conventional smear techniques , and the diagnostic efficacy of icc on smears processed by thin - layer lbc has been previously validated.15 - 17 up to the present time , there have been several reports regarding the diagnostic accuracy of csf cytology in patients with cns metastasis .
wasserstrom et al.5 reported a sensitivity of 54.4% in initial examination and 91.1% in subsequent examination .
even though we used implanted ventricular catheters when obtaining csf and lbc when preparing csf slides , results of our study showed much lower diagnostic rates than previous studies .
the discrepancy between results of previous studies and ours might be due to the different process of gathering csf ; unlike previous studies , we tried to evaluate the diagnostic rates of csf cytology using consecutive examination of csf samples from each patient .
moreover , in our study , samples were obtained from patients receiving adjuvant treatments such as chemotherapy and radiation therapy , which may have affected the diagnostic rates of csf analysis . from the viewpoint of daily practice
, our results may be more practical and accurate because most patients with cns metastasis are now managed with ancillary treatments.7 we could not analyze the results of csf examinations with statistics of sensitivity or specificity because not all cytology specimens had a concordant tissue biopsy .
in other words , the negative findings could not be directly considered as false negatives because we could not completely exclude the possibility that the negative findings resulted from true tumor regression due to adjuvant therapies . however , as shown in table 2 , results were distributed unevenly although all examinations were performed within very short intervals , even within the same day in some cases .
therefore , we suggest that the negative findings are not the results of tumor regression but false negative results . if so , the value of 41.3% can be regarded as sensitivity of csf cytology in patients being treated with adjuvant therapies due to cns metastasis .
first , several factors influencing the quality of csf cytology specimens should be investigated . in our study ,
however , this can not be the reason for the negative results because csf is physiologically acellular .
the volume of the submitted specimen can affect the diagnostic accuracy , but unfortunately this aspect was not evaluable because the amount of fluid was not promptly recorded .
dry artifact is one of the most important factors in determining the quality of csf slides . as mentioned earlier , we could maintain the quality of csf cytology by notifying clinicians of the importance of rapid transport .
however , specimen transport could not be controlled precisely and evenly because the specimens were transported by different clinicians with different time intervals .
there was no significant difference among negative results when grouped according to the sites of primary tumors ( data not shown ) .
taken together , the negative results should be regarded as a multifactorial phenomenon without a specific reason .
temporary csf cytology examinations are no longer sufficient for estimating clinical course because chemotherapy and optional radiotherapy are generally standard treatment modalities in patients with cns metastasis .
although the total number of cases included was not remarkable , this study is noteworthy in that we tried to evaluate the diagnostic rates of csf cytology in a novel way . by analyzing consecutive csf samples obtained within short - term intervals ,
we were able to evaluate the diagnostic rates of csf examination more precisely and more practically .
although the sensitivity of csf cytology as a diagnostic tool in patients with cns metastasis was lower than expected , even with the icc , we consider this result to be important and instructive as negative results should not be ignored or regarded as tumor regression . alternatively ,
continuous follow - up using csf cytology is essential for determining clinical course , and the results must be interpreted in conjunction with clinical and radiological findings .

Answer:
backgroundcerebrospinal fluid ( csf ) examination can be used to verify the presence of primary malignancies as well as cases of central nervous system ( cns ) metastasis .
 because of its importance , there have been several studies concerning the sensitivity of csf cytology . to determine the practical use and reproducibility of diagnoses based on csf cytology
 , we evaluated this test by analyzing cytology results from consecutive csf samples.methodsbetween july 2010 and june 2013 , 385 csf cytology samples from 42 patients were collected .
 the samples were gathered using a ventricular catheter and reservoir .
 csf cytology of all patients was examined more than two times with immunocytochemistry for cytokeratin.resultsprimary neoplastic sites and histologic types of patients ' metastatic cancer were diverse .
 the overall sensitivity for detecting malignancy was 41.3% .
 even within short - term intervals , diagnoses frequently changed.conclusionsour results were inconsistent , with low sensitivity , when compared to the results of previous studies .
 however , csf evaluation can still provide valuable diagnostic and prognostic information because adjuvant treatments are now routinely performed in patients with cns metastasis .
 negative csf cytology results should not be ignored , and continuous csf follow - up is essential for following the clinical course of patients with metastatic cancer involving the cns .


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:
despite many years of research efforts and impressive progress in knowledge of mechanisms of endometriosis development , the etiopathogenesis of the disease and exact cause of infertility in patients suffering from endometriosis still remain poorly understood .
none of the theories and models of endometriosis pathogenesis provide definitive explanation of the disease development , considering its different manifestations and various localizations .
recently published studies present new data on potential role of free radicals in endometriosis pathophysiology .
although the origin of the oxidative stress occurring in the peritoneal cavity in endometriotic patients is unknown , accumulating data suggest that increased iron levels , together with apoptotic endometrial fragments and activated macrophages , may promote prooxidant environment .
in addition , oxidative stress in endometriotic patients may potentially be induced by environmental factors , including dioxins or heavy metals [ 1 , 2 ] . in our preliminary work
we found significantly increased levels of ox - ldl in peritoneal fluid of women with stage iii / iv endometriosis compared to patients with follicle ovarian cysts .
however , peritoneal fluid oxldl concentrations did not differ significantly between patients with minimal / mild endometriosis and women from the reference group .
murphy et al .   showed increased low - density lipoprotein ( ldl ) oxidation in peritoneal fluid of patients with endometriosis , which may be a result of peritoneal cavity macrophages hyperactivity .
it was also proved that oxidized ldls stimulate monocyte chemotactic protein-1 ( mcp-1 ) expression in mesothelial and endometrial cells which provides direct evidence of oxidative stress role in etiopathogenesis of the disease . increased concentrations of lipid peroxidation end products , malondialdehyde ( mda ) , 8-isoprostane , and 25-hydroxycholesterol , were found in peritoneal fluid of infertile women with endometriosis [ 610 ] .
serum of patients with endometriosis , compared to healthy women , contains also significantly higher 8-isoprostane levels .
murphy et al .   showed that peritoneal fluid of patients with endometriosis contains increased concentration of lysophosphatidylcholine , another lipid peroxidation product with confirmed chemotactic properties for monocytes .
mda and 7-hydroxynonenal ( hne-7 ) expression were increased in endometriosis implants tissue ; however , both lipid proteins are also expressed in eutopic endometrium .
concentrations of antibodies against lipid peroxidation products were found to be increased in serum of women with endometriosis , with no immunoglobulins detected in their peritoneal fluid .
serum of women with endometriosis contains also elevated concentration of lipid hydroperoxide ( looh ) , and its levels correlate positively with the stage of the disease according to revised american fertility society classification .
peritoneal fluid of endometriotic patients contains oxidatively modified protein - lipid complexes , showing both chemotactic properties and ability to stimulate selected cytokines production . however , there are relevant data published in the literature according to which the concentrations of mda and mda - cu complexes demonstrate no significant differences , being comparable in peritoneal fluid of patients with and without endometriosis , showing also no significant correlation with the stage of the disease [ 1618 ] .
no differences were also found in peritoneal fluid concentration of another lipid peroxidation product , cholest-3,5-dien-7-one .
the objective of the study was to assess concentrations of oxidized low - density lipoproteins ( oxldl ) in peritoneal fluid ( pf ) of women with endometriosis .
clinically and histologically confirmed diagnosis established the following groups : women with endometriosis ( e , n = 110 ) and as the reference groups : patients with simple serous ( r1 , n = 78 ) and dermoid ( r2 , n = 41 ) ovarian cysts . in each case
the disease was found to be minimal ( e1 ) in 23 cases , mild ( e2 ) in 25 patients , moderate ( e3 ) in 39 women , and severe ( e4 ) in 23 cases .
subjects were not given hormonal therapy and/or anti - inflammatory medications for at least 3 months before laparoscopy .
medical history of the patients and basic clinical examination showed no general chronic diseases , except for the condition , which was the indication for laparoscopy .
similarly , no significant difference was found in the phase of menstrual cycle of the time of laparoscopic procedures between women in all study groups .
all patients signed an informed consent , and the lublin medical university ethics committee approval was obtained for the study .
all visible pfs were aspirated during laparoscopy from the anterior and posterior cul - de - sacs , under direct vision to avoid blood contamination .
samples were immediately centrifuged at 500  g for 5 minutes , and the supernatants were aspirated and stored at 70c until analysis .
oxldl concentration in the pf was measured in duplicate using a commercially available enzyme - linked immunoassay kit ( immundiagnostik ag , cat .
all data were tested with the shapiro - wilk test for normality . because data were not normally distributed , statistical significance between e and r groups was determined with the mann - whitney u test .
data are presented as medians ( me ) , minima ( min ) , maxima ( max ) , and lower and upper quartiles .
concentrations of oxldl in pf of patients with endometriosis were significantly higher compared to women with serous ovarian cysts ( p = 0.03 ) .
however , no significant difference in the pf oxldl levels was found between patients with endometriosis and women with dermoid ovarian cysts ( p = 0.4 ) .
levels of oxldl in pf of women with serous ovarian cysts were similar to those noted in patients with dermoid cysts ( figure 1 , table 1 ) . by analyzing concentrations of oxldl in pf of women with different stages of the disease
, it was noted that they were higher only in the subgroup of patients with stage iv endometriosis as compared to women with ovarian serous cysts .
no significant differences were found between concentrations of oxldl in pf of women with different stages of the disease ( table 2 ) .
pf oxldl concentration did not differ significantly between the subgroups of women in the follicular and the luteal phase of the menstrual cycle ( me , range : 71.5 , 1.21470  ng / ml versus 80.3 , 16.71870  ng / ml , p = 0.5 ) .
in our work , we demonstrated that peritoneal fluid oxldl concentration was significantly higher in patients with endometriosis than in women with serous ovarian cysts ; however , it did not differ significantly as compared to subjects with dermoid cysts . after analysis of data obtained in women with different stages of the disease , it was noted that these results are found only in patients with severe endometriosis . in case of minimal , mild , and moderate disease ,
to our knowledge , only murphy and colleagues investigated the possible role of oxldl in the pathogenesis of endometriosis .
based on a small number of cases , they found increased oxidation of low - density lipoprotein in women with pelvic endometriosis and increased levels of oxldl in the pf of patients with this disease .
our results agree with these findings . however , our data suggest that only the severe stage of endometriosis is associated with increased oxidation of low - density lipoprotein in the peritoneal cavity , probably as the result of an imbalance in prooxidant / antioxidant pf systems .
shanti et al .   demonstrated that women with endometriosis had increased serum concentrations of autoantibodies to markers of oxidative stress including oxldl .
data from our work indirectly confirm these results . based on many findings , there is an emerging concept of treating endometriosis as an autoimmune disease .
an increased incidence of endometriosis was observed in the group of women with autoimmune diseases such as multiple sclerosis , lupus erythematosus , psoriasis , crohn 's disease , hypothyroidism , hyperthyroidism , and rheumatoid arthritis .
endometriosis shares many similarities with other autoimmune diseases including elevated levels of cytokines , decreased cell apoptosis , and t- and b - cell abnormalities .
a variety of autoantibodies have been detected in patients with endometriosis patients , which suggests a polyclonal activation of b cells .
the most commonly reported types are antiendometrial , antiovarian antibodies , and autoantibodies against phospholipids , histones , and nucleotides
. other similarities between endometriosis and autoimmune diseases include familial occurrence , tissue damage , preponderance of females , and multiorgan involvement [ 21 , 22 ] .
lipid peroxidation processes are closely associated with the pathophysiology of autoimmune diseases . therefore , increased levels of oxidized ldl in pf of women with endometriosis support the theory of treating endometriosis as an autoimmune disease .
oxidized ldl induces secretion of numerous proinflammatory cytokines including macrophage colony - stimulating factor ( m - csf ) , interleukin-6 ( il-6 ) , and tumor necrosis factor  ( tnf- ) .
concentrations of these cytokines were found to be elevated in the pf of patients with endometriosis .
we can speculate that increased levels of oxidized ldl in the peritoneal cavity of women with severe endometriosis may be one of the factors responsible for increased levels of m - csf , il-6 , and tnf- in pf .
elevated pf concentrations of these cytokines promote adhesion , invasion , proliferation , and angiogenesis of ectopic endometrium and create an inflammatory environment in the peritoneal cavity in women with endometriosis .
.   demonstrated that oxldl caused an increase in accumulation of monocyte chemotactic factor-1 ( mcp-1 ) in the medium of cultured mesothelial and endometrial cells .
they also found that cells cultured in the presence of pf from endometriosis patients secreted more mcp-1 than those cultured with pf from subjects without the disease .
therefore , we hypothesize that increased concentration of oxldl may be responsible for , as demonstrated in other studies , higher concentrations of mcp-1 in the pf of women with endometriosis .
stimulation of mcp-1 production by increased pf levels of oxidized ldl may hypothetically be another factor responsible for the creation of proinflammatory environment in the peritoneal cavity of patients with endometriosis .
unfavorable changes in lipid profile are present not only in the pf of women with endometriosis .
it has been recently shown that plasma of patients with this disease contains higher concentrations of total cholesterol , low - density lipoproteins , high - density lipoproteins ( hdl ) and triglycerides as compared to healthy women .
although all lipoproteins were significantly elevated in endometriosis patients , the difference was most substantial for ldl levels , which were 38% higher in women with endometriosis .
verit et al .   found that patients with endometriosis displayed significantly lower serum levels of hdl and higher levels of triglycerides , total cholesterol , and ldl than women without the disease .
they also demonstrated that serum of women with endometriosis is characterized by significantly lower activity of paraoxonase-1 ( pon-1 ) , which negatively correlated with the progression of the disease .
this hdl - associated antioxidant enzyme with paraoxonase activity prevents ldl and hdl oxidation and is also responsible for the antioxidant effect of hdl .
therefore , authors speculated that unfavorable lipid profile combined with lower pon-1 activity in women with endometriosis may contribute to the increased susceptibility for the development of atherosclerosis . in conclusion ,
oxldl levels were significantly higher in the peritoneal fluid of patients with severe endometriosis than in women with serous ovarian cysts .
this suggests that disrupted oxidative status in the peritoneal cavity of women with endometriosis may play a role in the etiopathogenesis of the more advanced stages of the disease .
however , it can not be excluded that high oxldl levels are the result of more oxidant environment in the peritoneal cavity of patients with severe endometriosis than with less advanced disease .

Answer:
the etiopathogenesis of endometriosis still remains unknown .
 recent data provide new valuable information concerning the role of oxidative stress in the pathophysiology of the disease .
 it has been proved that levels of different lipid peroxidation end products are increased in both peritoneal fluid ( pf ) and serum of endometriotic patients .
 we assessed the concentration of oxidized low - density lipoproteins ( oxldl ) in pf of 110 women with different stages of endometriosis and 119 women with serous ( n = 78 ) or dermoid ( n = 41 ) ovarian cysts , as the reference groups .
 pf oxldl levels were evaluated by elisa .
 we found that concentrations of oxldl in pf of endometriotic women were significantly higher compared to women with serous but not dermoid ovarian cysts .
 interestingly , by analyzing concentrations of oxldl in women with different stages of the disease , it was noted that they are significantly higher only in the subgroup of patients with stage iv endometriosis as compared to women with ovarian serous cysts . in case of minimal , mild , and moderate disease ,
 pf oxldl levels were similar to those noted in reference groups .
 our results indicate that disrupted oxidative status in the peritoneal cavity of women with endometriosis may play a role in the pathogenesis of advanced stages of the disease .


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:
generalized convulsive status epilepticus ( gcse ) and non - convulsive status epilepticus ( ncse ) are important neurological conditions potentially associated with significant morbidity and mortality.1 even with the best current practice , the mortality of patients with refractory gcse is up to 50% .
therefore , there is an urgent need for new treatment options that can treat these seizures safely and more effectively than the current standard drugs.2 the most common treatment protocols for status epilepticus include an intravenous benzodiazepine , either lorazepam ( lzp ) or diazepam , as the initial antiepileptic drug ( aed ) therapy , followed by phenytoin ( dph ) or fosphenytoin .
phenobarbital ( pb ) is added if the seizures continue.3 a pharmacologically induced coma , using the barbiturates , propofol or midazolam , is also a frequently used therapy for refractory status epilepticus ( rse),2,4,5 which is defined as the persistence of discrete seizures without return to baseline , despite treatment with benzodiazepines and at least two adequate aeds.6,7 however , it requires artificial ventilation and hemodynamic support , and is associated with significant complications and increased mortality.2,4 topiramate ( tpm ) is an aed with demonstrated efficacy for a broad spectrum of seizure types8 ; it has multiple activities at receptors and ion channels that may be more effective than conventional anticonvulsants in treating rse.7,9 we report our experience with the use of tpm for the treatment of benzodiazepine - refractory status epilepticus ( se ) or recurrent seizures in 16 patients who are under severe medical complications such as systemic infection , renal dysfunction , hepatic dysfunction , and pancytopenia from bone marrow suppression .
we retrospectively identified patients with gcse or ncse who were treated with tpm at our hospital between july 15 , 2006 and august 10 , 2008 .
the medical records were reviewed for information regarding patient characteristics , associated medical conditions , type of se ( gcse or ncse ) , duration , abnormal laboratory findings , treatment history prior to administration of tpm , and outcome .
hepatic dysfunction was defined as an ast and alt > 200 mg / dl and renal dysfunction was defined as a serum creatinine > 2.0 mg / dl and a creatinine clearance < 0.6 .
anemia was defined as a hemoglobin < 12.0 g / dl , thrombocytopenia as a thrombocyte count < 150,000/mm and pancytopenia as a leukocyte < 4,000/mm with anemia and thrombocytopenia . administration of aeds , other than tpm , followed our hospital s protocol : lzp ( 4 mg ) was injected intravenously and dph ( 15 mg / kg ) or vpr ( 20 mg / kg ) were infused intravenously for 30 minutes .
the mixture was allowed to sit for several minutes to avoid clumping and then administered via syringe into a nasogastric tube .
the loading dose was individualized by patient ; 612 mg / kg / day , up to 1,000 mg / day .
the resolution of recurrent gtc and gcse was determined by cessation of clinical seizures , and confirmed by follow - up electroencephalopgrahy ( eeg ) . for ncse ,
from the database on se patients , 16 patients were identified for inclusion in this study .
no patient had a history of seizures or was receiving tpm or other aeds prior to admission .
the most common previous , co - morbid disease at the onset of seizures was sepsis ( n=8 ) .
the laboratory studies showed that 12 patients had hematological problems ( pancytopenia 8 , anemia alone 2 , and anemia with thrombocytopenia 2 ) .
seven patients had renal dysfunction , three patients had hepatic dysfunction only and another four patients had both renal and hepatic dysfunction .
the majority of patients had experienced gcse ( n=6 ) or ncse ( n=7 ) .
the mean tpm treatment dose was 637.5244.6 mg ( 3001,000 mg ) . within a few days
, 13 patients could experience their seizure control ( the mean duration , 3.72.6 days ; range 18 days ) , but the seizures of the other 3 subjects did not be terminated in spite of all efforts . none of the patients had a worsening of their cbc or blood chemistry profiles with the tpm treatment . for seven patients ,
the tpm was administrated after the failure of the loading of high doses of dph or vpr .
the administration of tpm was within 2 hours after the infusion of dph or vpr .
the overall outcome was described as follows : patient death ( n=11 ) , improved ( n=4 ) , transferred to another hospital ( n=1 ) .
the causes of 11 deaths were sepsis ( n=7 ) , fulminant hepatitis , sah , hypoxic brain damage , and herpes encephalitis .
we now represent two illustrative cases using tpm for controlling recurrent seizures from a variety of medical derangement .
a 48-year - old woman with no history of seizures was admitted to the hospital in poor health .
the patient was diagnosed with paroxysmal nocturnal hemoglobinuria ( pnh ) 20 years prior to admission and had been treated as an outpatient with oral steroids .
the routine blood tests on admission revealed pancytopenia ( hemoglobin 4.4 g / dl , hematocrit 13.3% , wbc 730/mm , and a platelet count of 52,000/mm ) and acute renal failure ( bun 126.5 mg / dl and creatinine 9.23 mg / dl ) .
continuous renal replacement therapy ( crrt ) was performed in the intensive care unit . on the third hospital day , gcse developed .
a loading dose of tpm ( 800 mg ) was administrated via a nasogastric tube . by the next day ,
however , intermittent brief seizures occurred several times under a maintenance dose of tpm ( 300 mg bid ) during the subsequent two days .
the diffusion - weighted mri revealed multifocal high signal intensity involving the occipital lobes , the right basal ganglia and the subcortical white matter of the prefrontal gyri on the diffusion and t2-weighted images .
the identified lesions showed increased values on the adc map , suggesting vasogenic edema or a posterior reversible encephalopathy ( pres ) .
the tpm was maintained at a dose of 200 mg bid , and there was no further seizure activity .
however , aspiration pneumonia and sepsis developed , and the patient died on the 15th hospital day .
a 56-year - old woman was admitted to the hospital with impaired mental status . the patient had a history of multiple myeloma ( stage iiia ) diagnosed three years prior to the admission
vad chemotherapy using vincristine , doxorubicin and dexamethasone was started . however , generalized seizures developed during the third cycle of chemotherapy , and the patient became unresponsive with her eyes deviated to the right side . the routine blood tests revealed pancytopenia ( hemoglobin 5.2 g / l , hematocrit 14.4% , wbc 4,570/mm , and a platelet count of 15,000/mm ) , and septic shock developed .
however , the blood culture revealed staphylococcus epidermidis , and she died on the 49th hospital day from septic shock .
we described 16 patients with gcse , ncse or recurrent gtc in whom tpm was administered alone or together with other aeds .
most patients with overt , convulsive status epilepticus respond to the first or second aed . however , when the patient fails to respond to this standard protocol during the initial treatment , the patient is considered  refractory  and requires additional , more aggressive treatment.3 rse is a life - threatening condition that carries a high mortality risk .
aggressive , early intervention permitting avoidance of a pharmacological coma can reduce the overall morbidity and mortality.4 current recommendations for the treatment of refractory status epilepticus include midazolam ( mdz ) , pentobarbital and propofol.10 however , respiratory depression and/or hypotension may result from this treatment , which may necessitate endotracheal intubation and/or vasopressor support .10,11 oral aeds such as tpm or lev , however , have much to offer if they can pre - empt these more aggressive managements.12 tpm has at least five independent actions at the cellular level13 : inhibition of kainate - evoked currents , enhancement of -aminobutyric acid ( gaba)-evoked currents , blockage of voltage - activated sodium channels , blockage of voltage - activated calcium channels , and inhibition of carbonic anhydrase isoenzymes .
the multiple mechanisms of action confer broad - spectrum efficacy against different seizure types and make tpm an attractive choice in the treatment of both partial and generalized se.14 since tpm has pleiotropic effects on neuronal excitability , a favorable pharmacokinetic profile and appears to have few side effects in the setting of rse , it is a reasonable therapeutic option in patients with se.3 tpm is also considered appropriate for treatment of patients with of hepatic or renal disease
. it does not significantly increase the risk of hepatotoxicity and renal disease is not a contraindication to the use of tpm.15 there are some reports on the use of tpm in se patients .
16 reported a patient with drug - resistant complex partial se who responded to tpm .
towne and colleagues described six adult patients with a variety of types of se who were unresponsive to conventional treatment , including two who also failed to respond to treatment with pentobarbital.7 a suspension of tpm administered by a nasogastric tube was effective in aborting the rse in all cases .
remarkably , no adverse events were observed and all six patients who survived and were discharged from the hospital .
bensalem et al . also described the use of tpm via a nasogastric tube in three patients with rse ( two with generalized seizures and one with partial seizures).14 tpm appeared to be very effective in stopping the rse ; in two of the patients that were resistant to either pentobarbital or propofol , and no adverse effects were noted .
patients who had se after therapeutic doses of at least two antiepileptic medications were given tpm , 10 mg / kg / d for consecutive days , followed by maintenance doses of 5 mg / kg / d . in each case , the se was stopped within 21 hours of the initial dose of tpm . in our study , the seizures of subjects were terminated both clinically and electrographically in 13 out of 16 patients .
the timing of improvement in our patients was within 18 days of starting the administration of tpm .
these findings are consistent with the pharmacokinetic properties of tpm and previous reports . in six cases , given tpm after loading with dph or vpr failed , tpm successfully stopped the seizures , even in medically complicated patients .
although seizures were stopped clinically and electrographically in the majority of our patients , the overall outcome was not very favorable in our study .
. the high mortality rate of the patients studied reflects the large number of leukemia and lymphoma patients treated in our hospital .
the majority of the patients studied had serious and often life threatening hematological problems such as pancytopenia or thrombocytopenia .
they had a variety of medical comorbidities , including systemic infection , hepatic or renal dysfunction and hematologic / oncologic disorders .
however , our results convincingly support that tpm is safe and effective in a special group of seriously ill patients .
we could find that tpm was not only safe but very effective for the control of recurrent epileptic seizures or se in patients with serious medical co - morbidities .
tpm may be considered as another treatment option when conventional protocols fail . a large prospective , randomized ,
controlled study is warranted to investigate the efficacy and safety of tpm for the treatment of se .

Answer:
background and purpose : the conventional therapeutic regimen for status epilepticus ( se ) may require artificial ventilation and hemodynamic support , and is associated with significant complications and increased mortality .
 we investigated the safety and effectiveness of topiramate ( tpm ) in patients with refractory se , who had medical complications such as systemic infection , renal dysfunction , hepatic dysfunction , and bone marrow suppression.methods:we analyzed the clinical features and therapeutic outcome in 16 patients with gcse , ncse or recurrent gtc in whom tpm was administered for its control.results:the majority of our patients had gcse ( n=6 ) or ncse ( n=7 ) .
 the common co - morbid diseases at the onset of seizures were hematological disorders ( pancytopenia 8 , anemia 2 , anemia with thrombocytopenia 2 ) and sepsis ( n=8 ) .
 twelve patients were under the renal and/or hepatic dysfunction . within a few days
 , 13 patients could experience their seizure control ( the mean duration , 3.7 2.6 days ) , but the seizures of the other subjects did not be terminated in spite of all efforts .
 no patients experienced a worsening of their cbc or blood chemistry profiles with the tpm treatment.conclusions:we could confirm that tpm was not only safe but very effective for the control of recurrent epileptic seizures or se in patients with serious medical co - morbidities .
 tpm may be considered as another treatment option when conventional protocols are ineffective .