Correcting rotational deformity following femoral nailing

Introduction

The incidence of rotational malalignment after femoral nailing has been reported to be at least 20%. If the deformity is recognised early, it can be corrected by changing the distal locking screw and rotating the bone prior to fracture union. It is common practice to use the same distal locking screw of the nail if this surgery is performed, however, there is a risk of the new drill hole “cutting out” into the old screw hole. The degree of rotational deformity that needs to be corrected to use the same distal locking hole without cut out of the screw has not been defined.

Method

Ten femora, five from cadavera and five synthetic (“Synbone”), were stabilised in a vice and then fitted with one distal transverse screw. The screw was then removed and a second distal transverse screw was inserted at the same level after variable amounts of rotation. The bone bridge between the drill holes was then measured and any cut out was noted.

Results

Both of the femora cut out when rotated 10°, and one when rotated 15°. The size of the bone bridge between drill holes in femora rotated by 20° was 3 mm. This bone bridge was increased to 4 mm when the femora were rotated by 25°, and 8 and 9 mm when rotated by 30°.

Conclusion

The amount of rotational deformity that needs to be corrected in order to use the same distal locking hole in a femoral nail is significant. In our study, this equates to a correction of at least 25°, but this is not a definitive value in practice. Particular attention must be paid to the location and size of the distal locking screw when correcting malrotation after femoral nailing, to ensure an adequate bone bridge between the two holes.     

Intramedullary nailing of proximal tibia fractures—An anatomical study comparing three lateral starting points for nail insertion

Introduction

Intramedullary nailing is challenging in proximal tibia fractures, associated with high rates of malalignment. To date, no studies report the potential of lateral tibia nail insertion to correct primary valgus malalignment, commonly seen in proximal quarter fractures.

Materials and methods

18 fresh-frozen cadaver lower extremities were used to simulate an AO/OTA 41-A3 fracture. Six nails (Expert Tibial Nailing System, Synthes, Salzburg, Austria) were inserted at the lateral third, six nails at the middle third and six nails at the medial third of the lateral tibia plateau. After nail insertion, alignment in the coronal plane was recorded.

Results

Mean varus malalignment was dependent on the entry point at the lateral tibia plateau. Mean varus malalignment was 16° if nails were inserted at the lateral third, 10° at the middle third and 4° after nail insertion at the medial third. If nails were inserted from the medial third, valgus malalignment was recorded in two specimens.

Discussion

The effect of correction of coronal malalignment in proximal tibia fractures is dependent on the point of nail entry at the lateral plateau. Primary valgus deformation up to 20° can be corrected by inserting tibia nails at the lateral third of the lateral tibia plateau. Surgeons should be aware of possible varus deformity and valgus malalignment despite lateral nail insertion.     

Dynamic Splinting for the Stiff Hand after Trauma: Predictors of Contracture Resolution

Study Design

Prospective cohort.

Introduction

Many variables are believed to influence the success of dynamic splinting, yet their relationship with contracture resolution is unclear.

Purpose of the Study

To identify the predictors of outcome with dynamic splinting of the stiff hand after trauma.

Methods

Forty-six participants (56 joints) completed eight weeks of dynamic splinting, and the relationship between 13 clinical variables and outcome was explored.

Results

Improvement in passive range of motion, active range of motion (AROM), and torque range of motion averaged 21.8°, 20.0°, and 13.0°, respectively (average daily total end range time, 7.96 hours). Significant predictors included joint stiffness (modified Weeks Test), time since injury, diagnosis, and deficit (flexion/extension). For every degree change in ROM on the modified Weeks Test, AROM improved 1.09° (standard error, 0.2). Test-retest reliability of the modified Weeks Test was high (intraclass correlation coefficient [2, 1] = 0.78).

Conclusions

Better progress with dynamic splinting may be expected in joints with less pretreatment stiffness, shorter time since injury (<12 weeks), and in flexion rather than extension deficits. Further research is needed to determine the accuracy with which the modified Weeks Test may predict contracture resolution.

Level of Evidence

2b.     

Oral candidiasis in patients receiving radiation therapy for head and neck cancer

Objective

To investigate oral candidiasis in patients with head and neck cancer before, during, and after radiation therapy, and to explore its association with clinical oropharyngeal symptoms.

Study Design

A cohort study.

Setting

University hospital.

Subjects and Methods

Subjects who received radiation therapy (RT) for the treatment of head and neck cancer were divided into two groups: an oral cavity irradiated group (OIRR group, n = 29) and an oral cavity nonirradiated group (ONIRR group, n = 17). A control group consisted of 18 healthy subjects. Patients were examined for signs of oral candidiasis before, during, immediately after, and one month after RT. Mouth and throat soreness (MTS), dysphagia, and xerostomia were evaluated by self-reported questionnaires, and associations between oral candidiasis and these symptoms were analyzed.

Results

The incidence of oral candidiasis during RT was significantly higher in the OIRR group (55.2%) than in the ONIRR group (11.8%). Similarly, the occurrence of xerostomia during RT was significantly higher in the OIRR group (86.2%) than in the ONIRR group (52.9%). In the OIRR group, the mean MTS score at the 20th fraction of RT was significantly higher in patients with candidiasis (mean ± SD, 5.8 ± 2.1) than in those with RT-induced mucositis without candidiasis (3.7 ± 2.0). In the OIRR group, 65.2 percent of patients who experienced dysphagia developed oral candidiasis, compared with only 10 percent in the ONIRR group.

Conclusion

Oral candidiasis concurrent with oral mucositis due to RT may increase oropharyngeal discomfort during RT.     

Severe and acute pancreatitis admitted in intensive care: a prospective epidemiological multiple centre study using CClin network database

Objectives

To describe the demographic characteristics, incidence of extra-abdominal hospital-acquired infections and outcome of patients admitted to intensive care unit (ICU) with severe acute pancreatitis.

Study design

A retrospective, observational multiple center (65 centers) analysis of prospectively acquired data.

Patients and methods

During 2 years, all consecutive admitted patients to ICU for severe acute pancreatitis in the centers participating in the nosocomial infections surveillance network CClin Sud-Est were included. Patients whose ICU stay was less than 48 hours were not included. Demographic characteristics, extra-abdominal hospital-acquired infections and clinical course were described.

Results

During the study period, 510 patients were included which represented 2 % of patients with a length of stay longer than 48 hours in the 65 participating ICUs. The global attack rate of extra-abdominal hospital-acquired infections (pneumonia, bacteremia, urinary tract or central venous catheter infection) was 23 % in overall patients and it was 33 % in the 294 mechanically ventilated patients. ICU mortality was 20 % in overall patients and it was 34 % in mechanically ventilated patients.

Conclusion

Severe acute pancreatitis represents 2 % of ICU stay longer than 48 hours. Its clinical course is frequently complicated by hospital-acquired infections and is associated with an high ICU mortality rate. This epidemiological observational study may be used for calculating sample size for future multicenter interventional therapeutic studies.     

Lower limb malrotation following MIPO technique of distal femoral and proximal tibial fractures

Objective

To determine the incidence of rotational malalignment in distal femoral and proximal tibial fractures using computed tomography (CT) scanograms following indirect reduction and internal fixation with the minimally invasive percutaneous osteosynthesis (MIPO) technique.

Design

Prospective Cohort.

Setting

Level I Trauma Centre.

Patients/Participants

A total of 27 consecutive subjects, and 14 proximal tibia and distal femur fractures.

Intervention

All patients underwent indirect reduction and internal fixation with a MIPO plating system. A CT scanogram to measure rotational malalignment between the injured and non-injured extremity was then undertaken.

Main outcome measure(s)

Femoral anteversion angles and tibial rotation angles between the injured and non-injured extremities were compared. Malrotation was defined as a side-to-side difference of >10°.

Results

A total of 14 postoperative tibias and 13 femurs underwent CT scanograms. Three females and 11 males with an average age of 38.1 years sustained proximal tibia fractures and six females and seven males with an average age of 55.8 years sustained distal femur fractures. The difference between tibial rotation in the injured and the non-injured limbs ranged from 2.7 to 40.0° with a mean difference of 16.2° (p = 0.656, paired T-test). Fifty percent of the tibias fixed with MIPO plates were malrotated >10° from the uninjured limbs. The difference between femoral anteversion in the injured and non-injured limbs ranged from 2.0 to 31.3° with a mean difference of 11.5° (p = 0.005, paired T-test). A total of 38.5% of the distal femurs fixed with MIPO plates were malrotated >10° from the uninjured limb.

Conclusions

Following fixation of distal femoral and proximal tibial fractures, the incidence of malrotation was 38.5% and 50%, respectively. The difference of the mean measures was significant for femoral malrotation; however, statistical significance could not be demonstrated for tibial malrotation. The incidence of malrotation following MIPO plating in this study is much higher than that quoted in previous studies.     

Continuous Real-time Viability Assessment of Kidneys Based on Oxygen Consumption

Background

Current ex vivo quality assessment of donor kidneys is limited to vascular resistance measurements and histological analysis. New techniques for the assessment of organ quality before transplantation may further improve clinical outcomes while expanding the depleted deceased-donor pool. We propose the measurement of whole organ oxygen consumption rate (WOOCR) as a method to assess the quality of kidneys in real time before transplantation.

Methods

Five porcine kidneys were procured using a donation after cardiac death (DCD) model. The renal artery and renal vein were cannulated and the kidney connected to a custom-made hypothermic machine perfusion (HMP) system equipped with an inline oxygenator and fiber-optic oxygen sensors. Kidneys were perfused at 8°C, and the perfusion parameters and partial oxygen pressures (pO₂) were measured to calculate WOOCR.

Results

Without an inline oxygenator, the pO₂ of the perfusion solution at the arterial inlet and venous outlet diminished to near 0 within minutes. However, once adequate oxygenation was provided, a significant pO₂ difference was observed and used to calculate the WOOCR. The WOOCR was consistently measured from presumably healthy kidneys, and results suggest that it can be used to differentiate between healthy and purposely damaged organs.

Conclusions

Custom-made HMP systems equipped with an oxygenator and inline oxygen sensors can be applied for WOOCR measurements. We suggest that WOOCR is a promising approach for the real-time quality assessment of kidneys and other organs during preservation before transplantation.     

Single-incision laparoscopic cholecystectomy (SILC): a refined technique

Background

Reports of decreasing the number of incisions in laparoscopic procedures began appearing in the 1990s. A recent spark in pursuing such an approach has been accelerated by natural-orifice transluminal endoscopic surgery.

Method

Several modifications in performing single-incision laparoscopic cholecystectomy (SILC) were introduced until it was possible to develop a simple and safe technique.

Results

SILC was completed in 61 of 71 operated patients. Fifty-five patients had SILC without cholangiography (average operative time, 49 minutes). Thirteen patients had SILC with cholangiography, 11 with negative results (average operative time, 67 minutes). Three patients needed additional trocars (bi-incision access surgery [BIAS]). None were converted to open procedures. Of the 69 patients with SILC or BIAS, 66 had same-day discharge, and 3 were discharged the following day.

Conclusion

SILC or BIAS is effective for gallbladder removal, with comparable lengths of stay, operative times, and safety as the traditional method, with better cosmetic results.     

Prompt correction of endotracheal tube positioning after intubation prevents further inappropriate positions

Study Objective

To determine whether the timely correction of endotracheal tube (ETT) positioning prevents further inappropriate positions.

Design

Prospective crossover study.

Setting

University-affiliated hospital.

Patients

44 adult, ASA physical status 1, 2, and 3 patients undergoing open or laparoscopic abdominal procedures.

Interventions

ETT positioning was verified by both auscultation and fiberoptic bronchoscopy (FOB), after intubation, and before extubation. In laparoscopic procedures, two additional measurements were performed: after maximal abdominal gas insufflation and with head-down position. An ETT in the bronchus or at the carina was considered an inappropriate placement. An ETT ≤ one cm from the carina was considered a critical placement.

Measurements

The frequency of inappropriate and critical ETT positioning with both auscultation and FOB and the number of ETTs that remained in an incorrect position despite repositioning.

Main Results

FOB detected 5 inappropriately positioned ETTs, 4 of which were also detected by chest auscultation (P = 0.99). Critical positioning was detected by FOB in 6 patients, three of which were also detected by auscultation (P = 0.24). There were 15 other "out-of-desired range” positions (out of the 3-5 cm range) - one placed too high and 14 placed too low, while 18 were placed within the range of positions. All patients with inappropriate ETT positioning were women (P = 0.005). Age, body mass index, Mallampati grade > 3, thyromental distance < 6 cm, or laryngoscopy grade ≥ 2 were not associated with either inappropriate or critical placement. No episodes of inappropriate or critical positioning were detected by FOB or auscultation at the end of surgery.

Conclusions

Early detection and prompt correction of inappropriate ETT positioning after intubation prevented further ETT migration into undesired positions.     

Cytokine Response to Ischemia/Reperfusion Injury in an Ex Vivo Perfused Porcine Liver Model

Background

We evaluated the degree of inflammatory response after ischemia/reperfusion injury by an extracorporeal normothermic autologous hemoperfusion of porcine livers.

Materials and Methods

Livers explanted from 7 pigs were perfused extracorporeally at 39°C with autologous blood. Serum samples were obtained hourly until 6 hours from the beginning of reperfusion and assayed for 9 different cytokines.

Results

Significant elevations in interleukin 6 (IL-6) and IL-8 were noted following reperfusion (P < .001), with both demonstrating an increase which followed a sigmoid curve; other cytokines that were assessed showed no significant change.

Conclusions

The ex vivo model excludes the liver from the influence of external systemic factors such as hormones, the autonomic nervous system, and other regulatory molecules produced elsewhere in the body, allowing the response to the ischemia/reperfusion injury to be studied in isolation and in considerable detail. Although this study examined a relatively short period, the increases in only IL-6 and IL-8 suggested that these are important molecules in the early phase after reperfusion.     

Refinements in pectus carinatum correction: the pectoralis muscle split technique

Background

The standard approach for correction of pectus carinatum deformity includes elevation of the pectoralis major and rectus abdominis muscle from the sternum and adjacent ribs. A postoperative restriction of shoulder activity for several weeks is necessary to allow stable healing of the elevated muscles. To reduce postoperative immobilization, we present a modified approach to the parasternal ribs using a pectoralis muscle split technique.

Methods

At each level of rib cartilage resection, the pectoralis muscle is split along the direction of its fibers instead of elevating the entire muscle as performed with the standard technique. From July 2000 to May 2007, we successfully used this technique in 33 patients with pectus carinatum deformity.

Results

After the muscle split approach, patients returned to full unrestricted shoulder activity as early as 3 weeks postoperatively, compared to 6 weeks in patients treated with muscle flap elevation. Postoperative pain was reduced and the patients were discharged earlier from the hospital than following the conventional approach.

Conclusions

The muscle split technique is a modified surgical approach to the parasternal ribs in patients with pectus carinatum deformity. It helps to maintain pectoralis muscle vascularization and function and can reduce postoperative pain, hospitalization, and rehabilitation period.     

Intravenous landiolol, a novel β(1)-adrenergic blocker, reduces the minimum alveolar concentration of sevoflurane in women

Study Objective

To investigate the effect of intravenous (IV) landiolol, a novel β₁-adrenergic blocker, on the minimum alveolar concentration (MAC) of sevoflurane in adult women.

Design

Prospective, randomized study.

Setting

University hospital.

Patients

42 ASA physical status 1 and 2 women, aged 24-57 years, who were scheduled to undergo elective abdominal surgery.

Interventions

Anesthesia was induced in all patients by vital capacity rapid inhalation induction of sevoflurane. In the landiolol group, administration of landiolol began when patients took a vital-capacity breath: 0.125 mg/kg/min for one minute and then 0.04 mg/kg/min. Normal saline was administered in the control group.

Measurements

MAC was determined by a technique adapted from the conventional up-down method.

Main Results

The MAC of sevoflurane was 2.2% ± 0.2% in the control group and 1.7% ± 0.2% in the landiolol group, a statistically significant difference (P = 0.0005).

Conclusions

IV landiolol reduces the MAC of sevoflurane in women by approximately 20%.     

Infant communicating hydroceles—do they need immediate repair or might some clinically resolve?

Purpose

Infant hydroceles that are communicating by history (fluctuation in size) or examination (reducible fluid) are often repaired soon after presentation. We have followed a series of infant boys with such hydroceles and reviewed their early natural history.

Materials and Methods

Since 1998, we have followed 174 infant boys presenting with an apparent communicating hydrocele without immediate surgical repair. All boys were initially seen before 18 months of age and most (168) by 12 months. Most had been full term at delivery, although 32 had been premature (<37 weeks' gestational age) and 11 extremely so (<32 weeks). Most boys (120) had bilateral hydroceles at presentation.

Results

Of the 110 boys followed to disposition, 69 (62.7%) had complete resolution without surgery by a mean age of 11.7 months. Forty-one patients (37.3%) underwent surgery for correction at a mean age of 14 months because of persistence in size or development of a hernia. Six developed a hernia during observation, none of whom had any episode of incarceration. Only 2 patients with apparent resolution subsequently had recurrence with a hernia. Age at presentation and gestational age at birth showed no effect on resolution. The hydroceles of 64 boys had improved in size after a mean follow-up of 13.9 months when last seen.

Conclusions

Many infant hydroceles that are communicating by history or examination do resolve clinically without surgery and deserve observation. Progression to hernia was rare in our experience and did not result in incarceration. Consequently, little risk is taken by initial observation.     

Polymorphisms of Interleukin-6 and Tumor Necrosis Factor Gene Promoters and Cardiorespiratory Function Following Liver Transplantation: A Preliminary Study

Introduction

The interindividual variability in cardiorespiratory function during liver transplantation (OLT) has been attributed to various factors, including polymorphisms in immunity genes known to affect the circulation levels of cytokines.

Aim

To evaluate polymorphisms of genes encoding for interleukin-6 (IL6) and tumor necrosis factor (TNF) in association with cardiorespiratory function in OLT.

Design

Prospective observational study.

Patients and methods

We studied 62 consecutive patients who had OLT performed in our hospital between 2004 and 2005. Polymorphisms at positions −308 and −409 of TNF gene, as well as those at −174 and −574 of IL6 gene were determined in all patients by means of PCR-RFLPs. Associations were carried out using chi-square tests and analysis of variance. A bilateral P < .05 was accepted as significant.

Results

No statistically significant associations were observed.

Conclusions

A relationship between the polymorphisms studied and respiratory function in OLT was lacking. These results must be interpreted with caution due to the limited sample size.     

A National Program Toward Improving Renal Health: Advancing Organ Donation Awareness

Background

Despite the national advocacy campaign for kidney transplantation from deceased donors in the Philippines 96% of kidneys transplanted into 721 kidney transplants from 1999 to 2001 came from living donors. A national survey on the knowledge, attitudes and perceptions of Filipinos on organ donation in 2001 showed factors that disadvantaged deceased organ donation to be poor understanding of “brain death,” religion, and fear of the operation. These concerns were addressed and another survey was conducted in 2005.

Objectives

To compare knowledge, attitudes, and perceptions of Filipinos on organ donation between 2001 and 2005, and compare the number of kidney transplants from deceased donors between 2001 until 2008.

Methods

Two surveys in 15 regions of the Philippines were conducted using multistage sampling. Using a structured questionnaire there were 2000 respondents in 2001, and 2140 in 2005. Analysis was performed using chi-square analysis.

Results

The majority of respondents knew about kidney donation. Between 2001 and 2005, there was increased awareness that transplants came from both living and deceased donors (37% to 41%) and a decline in those believing transplants came only from deceased donors (14% to 9%). Willingness to become a living (59% to 87%) or a deceased donor (35% to 49%) increased. The increase in transplantation from deceased donors from an average of 10 per year from 1999 to 2001 to 31 per year from 2006 to 2008.

Conclusion

Increased awareness about kidney donation among Filipinos, improved consent to become an organ donor, and an increase in kidney transplantation from deceased donors occurred from 2001 to 2008.     

Decreased Fresh Gas Flow Cannot Compensate for an Increased Operating Room Temperature in Maintaining Body Temperature During Donor Hepatectomy for Living Liver Donor Hepatectomy

Background

The purpose of this study was to compare the effect of various combinations of fresh gas flow (FGF) of anesthesia and different ambient operation room temperatures (ORT) on changes in nasopharyngeal temperature (NT) among living donors undergoing partial hepatectomy.

Methods

The anesthesia records of 167 patients were reviewed retrospectively. The patients were allocated into 4 groups: GI (n = 37): isoflurane in 2 L FGF and at typical ambient ORT (19°C-21°C); GII (n = 11) isoflurane in 1 L FGF and 1 L air at typical ORT; GIII (n = 31) isoflurane in 0.5 L FGF at typical ORT; and GIV (n = 88) isoflurane in 0.5 L FGF at ORT of 24°C.The changes in NT were compared using a two-way repeated measure analysis of variance (ANOVA) followed by Bonferroni post hoc tests.

Results

Changes of NTs of GIV were significantly higher compared with the other 3 groups, whereas the changes of NTs were the same among GI, GII, and GIII.

Conclusion

FGF of different volumes seemed to have no significant effect on intraoperative changes of NT in regular ORT. Low-flow anesthesia combined with ORT of 24°C provided significantly higher NTs at all measured points compared with GI, GII, and GIII.     

Assessment of the French surgical checklist: the experience of 17 French cancer centres

Introduction

The use of WHO checklist has been associated to a decrease of complication incidence and mortality. This control is mandatory since January the 1st 2010. Evaluation of the quality of documentation is important and includes filling rate, which is a reflexion of participant adhesion and analysis of the circumstances where the team answers “no” during the control.

Methods

This study concerned 17 among 20 French cancer centres. Percentage of documented checklist, exhaustivity of the answers in each checklist and “no” answers have been compared during two periods: January 2010 and October 2010.

Results

Rate of filled document is satisfactory and stable during the two periods (95.5% versus 95.8%). Exhaustivity was slightly better during the second period (64 and 68%, P = 0,039). Nevertheless, variability between centres was large; one centre improved and four centres worsened their scores. Rate of “no” answers was low and increased during the second period (1.5% in January 1.9% in October P < 0.001). They mainly concerned antibiotic administration and at a lesser degree bleeding risk, the name of the procedure, equipment problem to be addressed and postoperative management.

Discussion

There is a large discrepancy between centres and for a given centre in reporting quality. Significant progress should be expected using target improvement. This approach implies multiple critical analysis of checklist content in each hospital and in multicentre enquiries.     

Active surveillance of small renal masses: progression patterns of early stage kidney cancer

Background

Most early stage kidney cancers are renal cell carcinomas (RCCs), and most are diagnosed incidentally by imaging as small renal masses (SRMs). Indirect evidence suggests that most small RCCs grow slowly and rarely metastasize.

Objective

To determine the progression and growth rates for newly diagnosed SRMs stratified by needle core biopsy pathology.

Design, setting, and participants

A multicenter prospective phase 2 clinical trial of active surveillance of 209 SRMs in 178 elderly and/or infirm patients was conducted from 2004 until 2009 with treatment delayed until progression.

Intervention

Patients underwent serial imaging and needle core biopsies.

Measurements

We measured rates of change in tumor diameter (growth measured by imaging) and progression to ≥4 cm, doubling of tumor volume, or metastasis with histology on biopsy.

Results and limitations

Local progression occurred in 25 patients (12%), plus 2 progressed with metastases (1.1%). Of the 178 subjects with 209 SRMs, 127 with 151 SRMs had > 12 mo of follow-up with two or more images, with a mean follow-up of 28 mo. Their tumor diameters increased by an average of 0.13 cm/yr. Needle core biopsy in 101 SRMs demonstrated that the presence of RCC did not significantly change growth rate. Limitations included no central review of imaging and pathology and a short follow-up.

Conclusions

This is the first SRM active surveillance study to correlate growth with histology prospectively. In the first 2 yr, the rate of local progression to higher stage is low, and metastases are rare. SRMs appear to grow very slowly, even if biopsy proven to be RCC. Many patients with SRMs can therefore be initially managed conservatively with serial imaging, avoiding the morbidity of surgical or ablative treatment.     

The production of reactive oxygen species in tacrolimus-treated glial cells

Objective

After organ transplantation, some patients suffer from mild neurological symptoms, such as tremor, to severe complications, including seizures and encephalopathy. These neurological side effects can be caused by immunosuppressants such as tacrolimus. However, the mechanism of encephalopathy by tacrolimus is not fully understood.

Methods

We measured the production of reactive oxygen species (ROS) in glioma cells after tacrolimus treatment. Tacrolimus added to glioma cells was incubated for 60 minutes at 37°C. The production of ROS was evaluated by measuring the fluorescent product from the oxidation of an oxidant-sensitive 2′,7′-dichlorofluorescin using VICTOR^3TM multilabel counter.

Results

Tacrolimus resulted in the production of the ROS in glioma cells. The production of the ROS was increased in time-dependent fashion.

Conclusions

These findings indicated that the tacrolimus may contribute the neurological side effects by ROS production.