BC MENTAL HEALTH CENTRE AND SUBSTANCE ABUSE	Patient Loc-Svc:  CPE-MH  DISCHARGE SUMMARY  Admitted:	31/01/2018  (DD/MM/YYYY) Discharged:	[**2020-09-28**]  (DD/MM/YYYY)   CAPE UNIT DISCHARGE SUMMARY  Date of admission:  [**2020-10-27**].  Date of discharge:  [**2020-10-28**].  MEDICATIONS ON ADMISSION None (sertraline prescribed).  DISCHARGE MEDICATIONS 1.	Fluoxetine 10 mg daily x1 week, likely will increase to a target dose of 30 to 40 mg. 2.	Lorazepam 0.5 mg sublingually q.1h p.r.n. to a maximum of 1 mg per day, a 7 tablets prescription.  ADMISSION DIAGNOSIS Major depressive disorder, with suicidal ideation.  DISCHARGE DIAGNOSIS Major depressive disorder, with suicidal ideation.  Anxiety traits and obsessive traits also present.  TREATMENT/COURSE IN HOSPITAL [**First Name8 (NamePattern2) 1**] [**Last Name (NamePattern1) 2**] is a 14-year-old girl who lives with her family in Vancouver, British [**Location (un) 3**].  She has divorced parents and spends half time with her mother and half time with her father and stepmother.  [**Female First Name (un) 1**] was admitted on [**2020-10-27**], after her 2nd presentation to the emergency department in 2 days.  She had significant suicidal ideation on her time of admission, and was seen the next day for assessment and planning.   In interview, [**Female First Name (un) 1**] presented as depressed.  She endorses multiple depressive symptoms including loss of appetite, loss of energy, decreased sleep, decreased concentration, negative self talk and feelings of guilt and worthlessness, sadness, and lack of interest in normally enjoyable behaviors.  She states that these things have been going on for a very long time and she cannot remember the last time, she felt well.  She was just discharged from the hospital yesterday following presentation to emergency department for thoughts of wanting to cut her wrists, and she states that when she was discharged, the day was going relatively well although she had the background suicidal ideation, and then when she went to see her therapist was able to do a safety plan.  However, shortly after that, she "quickly unraveled" and became suicidal once again and had to come to the hospital.  Because of the rapid representation to the emergency department admission was an obvious choice and [**Female First Name (un) 1**] was admitted to the CAPE unit without any incident.   [**Female First Name (un) 1**] did a lot of self isolation on the unit, primarily owing to the fact that she finds herself to be relatively socially awkward and anxious, and she had a very hard time introducing herself on the unit.  As well, the unit milieu was somewhat intense with a patient with high needs, and she had some concerns that she might not be safe on the unit.  This was not paranoia, it was well founded.  [**Female First Name (un) 1**] spent her time in the patient room, drawing, and then when her mother brought a book, reading.   [**Female First Name (un) 1**] states that she has a good relationship with Dr. [**Last Name (STitle) 4**] and looks forward to seeing her weekly.  She notes that things have been deteriorating despite seeing Dr. [**Last Name (STitle) 4**] but was quite insistent that she fell that Dr. [**Last Name (STitle) 4**] was being helpful for her and wanted that relationship to continue.  She did agree that she needs to try and start medication, and the prescription has been given but she had not yet taken it (only prescribed a few days ago).  When we reviewed medication options, she was willing and eager participant, asking appropriate questions but clearly wanting to feel better.   [**Female First Name (un) 1**] describes a long-standing suicidal ideation that has never quite left.  She states the last few days have gotten more intense, however she also reaches out for help and recognizes that things need to get better.  She is able to identify a number of future goals such as going to [**Location (un) 5**], graduating high school, becoming a microbiologist, seeing her friends, etc.  She states that the thoughts of death and dying sometimes overwhelm her and recently she has been feeling less swayed by the idea that people around her would suffer and feeling more that she has such a failure that people around her would do better if she was dead.  During our conversation she was quickly able to identify that as a maladaptive thought, and something that was more like "the depression talking."  She admits that her depression has gotten the best of her over the last little while and she has noticed a significant decline.  She finds it very hard to concentrate at school, even though she is getting very good marks.  [**Female First Name (un) 1**] was able to share that she would like to get better and was willing to take medication, and by the end of our interview time she was working on a discharge plan.   A meeting with mother revealed significant concern for the deterioration despite therapy.  Mother was on board with medication and needed little convincing.  Father was away in the UK but mother felt that their goals were aligned and father was available for a followup meeting that we will be scheduling.  Mother agreed to the discharge plan as outlined below, and [**Female First Name (un) 6**] stepmother and grandmother also joined for the family meeting in consideration of the same.   [**Female First Name (un) 1**] had no major incident on the unit and did relatively well.  She received psychoeducation very well with respect to medication and continues to endorse to want to see Dr. [**Last Name (STitle) 4**].  She seemed to get along well with the writer and was happy to see me in follow up appointment next week, and when given the opportunity to stay in hospital overnight 1 more night or go home, [**Female First Name (un) 1**] chose to go home.  She seemed to be in a good frame of mind, and understood that she could come back to the hospital at any time.  She completed the safety plan with us which was similar to the one that she had with Dr. [**Last Name (STitle) 4**] the previous day.  MENTAL STATUS EXAMINATION ON DISCHARGE [**First Name8 (NamePattern2) 1**] [**Last Name (NamePattern1) 2**] is a 14-year-old, slender, female, who looks her stated age.  She had dark circles under her eyes.  She was somewhat slow in her movements but not fully bradykinetic.  She has good hygiene and good posture, was reciprocal and interactive during the conversation.  Her language use was good and she was fluent in English.  She was able to articulate herself clearly.  Thought form was organized and goal directed.  Thought content was free of any major delusions but she has overall depressive content with significant lack of self-esteem and over emphasis on negative judgment.  Perceptual abnormalities were denied.  Affect was sad but she was able to brighten up and showed good sense of humor in response to jokes.  Mood was described as low and sad.  Insight and judgment were appropriate for her age, and suicidal thinking is ongoing and passive, with no active thoughts today.  RISK ASSESSMENT [**Female First Name (un) 1**] obviously struggles with long-standing suicidal ideation but she has a life long history of self-injury with multiple opportunities for further injuries that she has not seized upon.  She is future focused and amendable to psychotherapeutic, as well as pharmaceutical treatment, and was able to construct a significant and reasonable safety plan.  She has good supervision, good access to followup, and with her visit here that she is familiar with how to reach out to emergency services and get hospital help.  [**Female First Name (un) 1**] was an active participant in her care and was a problem [**Name (NI) 7**], and though suicidal ideation is a major concern and I will always worry about her risk for suicide, at the time of her admission, and in planning for her discharge, her risk of death by suicide seems modest, particularly in the light of her intractability and problem solving.  I have no doubt that she is struggling with depression but she was hopeful that medication treatment be helpful for her and liked the idea of using emergency medications instead of entertaining suicidal thoughts for very long.   Overall, I do not think a longer hospitalization is warranted, and the exposure to risk on the unit with our more activated patient's right now does not seem a large benefit compared to her discharge to her loving and well supervised home, when she is willing and able to engage in both voluntary, as well as emergency treatment by accessing Hospital.  With rapid followup and ongoing psychotherapeutic care, I believe that discharge is appropriate.  PLAN 1.	Follow up with Dr. [**Last Name (STitle) 4**] as previous. 2.	I will contact Dr. [**Last Name (STitle) 4**] by phone at [**Telephone/Fax (2) 8**], and update regarding the admission today.  As well, her school counselor, Mr. [**Last Name (Titles) 9**], who is available at [**Telephone/Fax (2) 10**] or [**Telephone/Fax (2) 11**], to discuss reduction of school burden. 3.	We started medication as indicated above. 4.	[**Female First Name (un) 1**] will come see me for followup on [**2020-11-04**], at 4:30 p.m.  I will see her weekly while medication starting. 5.	We will be available for [**Female First Name (un) 1**] long-term.  If she needs to come back to the hospital she can present to the emergency department at any time, as well I provided my e-mail address and I am very comfortable with [**Female First Name (un) 1**] or her family emailing me as I am available generally the next day for any urgent concerns.   It was a pleasure seeing [**Female First Name (un) 1**] and her family during this stay and we wish her the very best in the future.   [**Signature 12**] Dictated By:  [**First Name4 (NamePattern1) 13**] [**Last Name (NamePattern1) 14**], MD Psychiatry  TB/MODL Job #:  332146 Doc #:  34369705 D:  [**2020-09-28**] 17:03:45 T:  [**2020-09-28**] 18:36:52


BC CHILDREN'S HOSPITAL	Patient Loc-Svc:  T1ED-MH  DISCHARGE SUMMARY  Admitted:	13/03/2018  (DD/MM/YYYY) Discharged:	19/03/2018  (DD/MM/YYYY)    MOST RESPONSIBLE DIAGNOSIS Adjustment disorder.  PRE-ADMIT DIAGNOSIS 1.	Major depressive disorder. 2.	Generalized anxiety disorder.  POST-ADMIT DIAGNOSIS 1.	Major depressive disorder. 2.	Generalized anxiety disorder.  PRE-ADMISSION MEDICATION 1.	Fluoxetine 40 mg p.o. daily. 2.	Clonazepam 0.25 mg p.o. q.a.m. and 0.5 mg p.o. at bedtime.  MEDICATIONS ON DISCHARGE 1.	Citalopram 10 mg p.o. daily with a goal of increasing every week until a target dose of 40 mg p.o. daily is reached. 2.	Clonazepam 0.25 mg p.o. q.a.m. 0.25 mg p.o. at bedtime.  The goal with the clonazepam is to taper and discontinue over a 2-week period of time.  DISCHARGE DISPOSITION [**Female First Name (un) 1**] was decertified and discharged home to the care of her parents.  POST-DISCHARGE FOLLOW-UP [**Female First Name (un) 1**] will follow up with the Pacifica Spirits Mental Health team.  RISK ASSESSMENT On the day of discharge, [**Female First Name (un) 1**] reported that, despite having ongoing suicidal ideations "at the back of her mind," that currently she did not have any specific plans or intent.  As such, her acute risk of suicide or significant self injury is low.  However, [**Female First Name (un) 1**] has a longstanding history of having chronic suicidal ideations and as a result, will always be at risk of completed suicide.  Despite this, the potential lethality of her plans remain of low risk.  Her previous attempts of suicide and self-harm behavior include cutting herself, threatening to jump out of moving cars, or jumping down a flight of stairs.  However, upon further exploration of her suicidal intent during her current admission, [**Female First Name (un) 1**] disclosed that there where several protective factors that prevented her from completing or going through with her plans which included the love that she has for her parents and having a relatively low pain tolerance. As such, [**Female First Name (un) 1**] remains a chronic risk for suicide or significant self injury; however, her current acute risk is low.  TREATMENT/COURSE IN HOSPITAL [**First Name8 (NamePattern2) 1**] [**Last Name (NamePattern1) 2**] is well known to the CAPE unit from previous brief admissions and followup with Dr. [**Last Name (STitle) 3**] for medication management for her depressive and anxiety symptoms.  Please see past consultations and discharge summaries for complete details.   [**Female First Name (un) 1**] was brought to the ER on [**2020-12-07**], by the RCMP after her mother had found her cutting her wrists and after [**Female First Name (un) 1**] had attempted to jump out of the window as a suicidal attempt.  She was assessed in the ER and certified under the Mental Health Act for further management and safety concerns.   Over the course of her admission, [**Female First Name (un) 1**] did endorse having suicidal ideations while admitted in the CAPE unit, however, on daily assessments, began to deny having a specific plan or intent.  She described how she could not identify any recent triggers or stressors that might have affected her presentation, though [**Female First Name (un) 1**] did disclose that she always has a plan at the back of her mind for how she would commit suicide when the opportunity presents itself.  Despite this, she remained well settled on the unit and was compliant with her treatment plan.  [**Female First Name (un) 1**], though, did mention how she felt that the fluoxetine 40 mg p.o. daily that she was taking was not entirely effective in managing her depressive and anxiety symptoms.  As a result, [**Female First Name (un) 1**] was started on citalopram 10 mg p.o. daily, and the fluoxetine was discontinued.   In addition, [**Female First Name (un) 1**] had psychological testing done with Dr. [**Last Name (STitle) 4**], which [**Female First Name (un) 1**] said she found very helpful and therapeutic.  Dr. [**Last Name (STitle) 4**] also worked with [**Female First Name (un) 1**] on formulating and modifying her current safety plan.   Several family meetings were held with her parents, where support was provided regarding [**Female First Name (un) 5**] safety, and approaches were suggested on how her parents should manage when [**Female First Name (un) 1**] has ongoing suicidal ideations or is engaging in self-harm behaviors.  [**Female First Name (un) 5**] parents said that they felt well supported with the plan and also felt safe with regard to her being discharged under their care.   On the date of her discharge, a meeting was held with her parents and [**Last Name (un) 6**], from Pacific Spirit, regarding post discharge followup with the mental health team as well as starting the process of referring [**Female First Name (un) 1**] for DBT therapy.   On discharge, [**Female First Name (un) 5**] mental status was observed as being more engaged in conversation, she volunteered providing information on her own rather than being prompted.  She was cooperative and more accessible.  Reliability still remained questionable, but rapport was easier to establish compared to previous interactions.  Her eye contact was consistent, and her speech was normal in rate, rhythm, tone, and volume.  Her thought form was organized, coherent, and goal and future oriented.  Despite endorsing current suicidal ideations, she denied having a plan or intent and felt safe to be discharged home.  She denied any delusional content, as well.  Her mood subjectively was "improving," and her affect was euthymic and reactive.  Her cognition was grossly intact, and she denied any auditory hallucinations or visual hallucinations.  Her insight and judgment were both deemed as being fair.   Thank you for involving us in this patient's care.   [**Signature 7**] Dictated By:  [**First Name9 (NamePattern2) 8**] [**Last Name (un) 9**] (Res), MD  [**Signature 7**] Dictated For:  [**First Name4 (NamePattern1) 10**] [**Last Name (NamePattern1) 3**], MD Psychiatry  VP/MODL Job #:  459275 Doc #:  35087473 D:  20/03/2018 13:17:37 T:  20/03/2018 15:07:09


BC MENTAL HEALTH CENTRE AND SUBSTANCE ABUSE	Patient Loc-Svc:  CPE-PM  OUTPATIENT PSYCHIATRY CLINIC  DISCHARGE SUMMARY  Admitted:	[**2020-12-29**]  (DD/MM/YYYY) Discharged:	  (DD/MM/YYYY)    Date of admission:  [**2020-12-29**].  Date of discharge:  [**2020-12-30**].   Admission medications:  1.	Risperidone 1 mg daily. 2.	Fluvoxamine 125 mg daily. 3.	Doxycycline 100 mg daily. 4.	Feramax 300 mg daily. 5.	Melatonin 10 mg nightly. 6.	As needed:  Benadryl.  Discharge medications:  No change to any medications except:  1.	Risperidone will be slightly increased by 0.125 mg every week for a target dose of 1 mg p.o. b.i.d. 2.	Benztropine has been added as a p.r.n. medication in case of any extrapyramidal side effects.   3.	Doxycycline, Feramax, Melatonin, and fluvoxamine are unchanged.  ADMISSION DIAGNOSIS Autistic spectrum disorder, borderline intellectual disability, aggression in the context of previous.  DISCHARGE DIAGNOSIS Autistic spectrum disorder, borderline intellectual disability, aggression in the context of previous.  COURSE IN HOSPITAL Please see the excellent consultation note by Dr. [**First Name4 (NamePattern1) 1**] [**Last Name (NamePattern1) 2**] regarding the admission of Noorayne Ladha.  I have known Noorayne from previous consultations in the emergency department, and this admission summary was very helpful in catching me up to the things that have recently happened.  Noorayne had a very short stay on the CAPE unit which was uneventful from any safety events.   Briefly, Noorayne was admitted to hospital for endorsing suicidal ideation in the context of conflict with his family, who had removed equipment that he usually uses for entertainment (Nintendo DS, computer) after he broke a laptop in frustration.  During the next day, he became very upset with respect to his loss of privileges, had to be removed from school after getting very upset, and then when he was at home he indicated that he wanted to hurt himself.  Mother drove him to hospital.   Noorayne spent the evening sleeping, and was very easy to be interviewed on the next day of admission.   Meeting with Noorayne, it was clear that he had returned to his baseline.  He had perceived some slights with respect to his mom taking away his electronics, but he admitted that he took things too far and felt like he said things that he did not mean.  He autistically explained many problems that he has with the world, and on the face of it these are concerning things to be said.  For example, he believes that the world would be better without any children.  He believes that the world would be better if someone would kill [**First Name4 (NamePattern1) 3**] [**Last Name (NamePattern1) 4**].  He believes that if there were no banks or money, that people would be happier.  He also makes misogynistic and racial comments, sharing with me that he wished that there were "no women, and no black people."  He says these very matter of factly, and I do not believe his intention is to create any offense, but it is clear that by expressing these things he is going to create significant concern for people around him.  I shared that with him, and he admitted that he should not say those things out loud.  I believe that in his autistic world, he is very influenced by his online hang outs.  He is particularly interested in two Internet web sites, Reddit, and 4 [**Last Name (un) 5**], both places where if one wants to, they can descend into a world of significant misogyny, racism, and hatred.  I believe that Noorayne is very influenced by things that he reads online, and is very powerfully captured by funny things such as the means or jokes, even at the expense of misogyny or racism.  I shared with Noorayne that he needs to make sure that he is looking at things that are appropriate and remembering that people online can be manipulative.  Noorayne superficially accepts this but also believes that he is part of the group and believes that he could lead "a revolution against the world."   Noorayne admits that he should not have been aggressive towards his mother and should not have threatened suicide.  He is no longer suicidal.  He feels like going home is appropriate, and felt like he had no difficulties with being discharged today.  He wanted to be a part of any family planning meetings, and was receptive to the idea of me meeting with his parents first.   When parents came in for a meeting, they shared that his behavior had declined since March, with a reduction of risperidone from a higher dose which caused significant oculogyric events, down to 1 mg which has not led to any oculogyric events but has been less helpful with respect to containing his aggression.  We explored options with respect to treating this and parents selected the treatment plan below, which was our recommended treatment plan.   Parents had no concerns in taking Noorayne home and felt that he had returned to baseline.  They were appreciative of his short stay on the unit but they do miss him and the unit was active with respect to distress by other patients, so they were worried about the influence of fear on Noorayne.  They elected to take him home on discharge.   Noorayne was discharged easily with no complications on [**2020-12-30**], at approximately 2 p.m.  IMPRESSION If feels like Noorayne was doing better at 2 mg of risperidone but he was having events that were quite convincingly oculogyric crises.  These events are dangerous with respect to their connection to other central dystonias, which can include laryngospasm.  For this reason, it is very important to weigh the oculogyric crisis' significant negative with respect to risperidone.  At the same time, the risperidone was restarted from a switch from aripiprazole at a high dose and ramped up very quickly, and with his previous good response to risperidone and his lack of any dystonia today, we felt that it was appropriate to try and increase his risperidone gradually.  Another option that was considered was to keep his risperidone exactly where it was, but to add clonidine.  In the pursuit of not adding too many medications together, he is already on quite a list, we elected to do a cautious re titration of risperidone, watching out for any oculogyric events.   With respect to his behavior and language, it will always be shocking and in his autistic world, he is not causing any offence by his statements.  He comes across as legitimately a charming person, but when you delve into his thinking it is clear that he is very black and white, and he has been heavily influenced by racial and misogynistic posts online.  That all being said, he treats people with respect and says the right thing when he knows he should.  Some of his more outlandish statements are very difficult to digest, but I believe that there is no current evidence of any significant violence towards others or his threats that he has mentioned to other people do not seem to have significant weight behind them.  I know that he has lost school standing and had to switch schools because of a threat towards principal, and he says some things such as "wanting to kill all  children which are obviously unsettled.  At the same time, his autistic spectrum disorder is not treatable, and he is well contained and responds very well to a behavioral approach.  He holds himself to a very high standard and I believe his greatest risks are when he is frustrated doing self injury or attempting to elope.  I do not believe that he is at risk for homicidal acting out, either injuring others or trying to kill others.   When it comes to his suicide risk, his autism and borderline IQ are protective factors.  That being said, in frustration I could see him hurting himself.  For this reason, frustration tolerance is one of our biggest goals, which I hope that the medication changes will accommodate.  As well, I have encouraged parents not to try too many behavioral things right now while he is clearly unsteady.   For all these reasons, I felt that discharge from hospital was appropriate, there is a chronic risk of hurting himself, and he has previously made threats against others, however I do not believe that these threats or violent parameters will change with any inpatient treatment, and a gradual titration of risperidone is most appropriately done as an outpatient.  Watching Noorayne react so negatively to emotion of the unit (another patient became quite distressed) was also quite convincing that the hospitalization was relatively traumatic for Noorayne.  With parents being on board with the safety plan, demonstrating excellent judgment with respect to managing Noorayne, and Noorayne's willingness to try to take things a little bit easier and try a new medication, discharge was appropriate.  TREATMENT PLAN 1.	Increase gradually risperidone by 0.125 mg every week to a target dose of 2 mg (1 mg b.i.d.). 2.	Mother will keep look out for any oculogyric events, if they happen, she has benztropine on order to be able to give him.  If the benztropine does not work I have instructed her to bring him to the hospital. 3.	If risperidone is not able to come back to the full dose at 2 mg total dose daily, going back to 1 mg daily and using clonidine, with an eye to possibly switching to clonidine or guanfacine monotherapy should be the next course of action. 4.	We set up appointments with Dr. [**Last Name (STitle) 6**] for followup with respect to dystonia.  I will check in for any appointments that Dr. [**Last Name (STitle) 6**] can not make, and mother can set up an appointment with me to check in.  We are hopeful that the dystonia checks can happen biweekly, and if there is any challenges with increasing the doses, we can hold at our current dose or consider going to the clonidine.  Please note that as of today, at 1 mg of risperidone there was no dystonia or clonus noted.   It was a pleasure working with Noorayne and we wish him the very best in the future.   [**Signature 7**] Dictated By:  [**First Name4 (NamePattern1) 8**] [**Last Name (NamePattern1) 9**], MD Psychiatry  TB/MODL Job #:  498284 Doc #:  35329425 D:  [**2021-01-28**] 15:56:06 T:  05/04/2018 16:54:53


BC CHILDREN'S HOSPITAL	Patient Loc-Svc:  T1ED-MH  DISCHARGE SUMMARY  Admitted:	26/04/2018  (DD/MM/YYYY) Discharged:	  (DD/MM/YYYY)  This report is provided to support continuity of care.  Blanks/discrepancies are indictated by [**Signature 1**].  Please contact the dictating author for clarification.  If you are the dictating author, please fax any corrections or clarification to: Transcription Services [**Telephone/Fax (2) 2**]  WORKING DSM-V DIAGNOSES 1.	Borderline personality traits versus disorder, 301.83 (we have discussed that given [**Location (un) 3**] age as well as seeing him during a time of crisis, it is not appropriate to give him a full diagnosis of borderline personality disorder). 2.	Unspecified depressive disorder, 311. 3.	His unspecified anxiety disorder, 300. 4.	Cannabis use disorder, mild, 305.20. 5.	Parent-child relational problem, 361.20. 6.	Intellectual disability, psychoeducation test conducted in spring of [**2020**] (written language output disorder, arithmetic disorder, and a writing output disorder).  MEDICATIONS ON DISCHARGE 1.	Fluoxetine 20 mg p.o. q.a.m.  Please note that we have changed the dosing to morning dosing, as evening dosing can be quite agitating and may have interrupted in [**Location (un) 3**] sleep pattern.  He was given a 1-month supply with no repeats. 2.	Lorazepam sublingual 0.5 to 1 mg q.4h p.r.n. to a maximum of 4 mg in 24 hours.  We have given him a prescription of 30 tablets with no repeats.  The family is aware to use this as part of his safety planning and acute distress episodes, especially in the first month after discharge. 3.	Trazodone 25 mg p.o. nightly for initial and mid insomnia.  Given for a 1-month supply with no repeats. 4.	Melatonin 3 to 15 mg p.o. nightly 30 minutes before bedtime over-the-counter.  THERAPEUTIC RECOMMENDATIONS UPON DISCHARGE 1.	Safety planning:  We have gone over explanation of safety planning with both [**Location (un) **] individually as well as with both parents during the discharge meeting today.  We have also filled out [**Signature 1**] form which was done in the emergency department, where he rates as low suicide risk.  [**Location (un) **] is actually very insightful and displays good judgment and is able to ask for help when he is feeling distraught.  Although he had a recent overdose of "20 tablets of ibuprofen" in the context of altercation at band camp in Whistler 48 hours ago, there was very vague evidence of the same.  It is important to note that his ongoing suicidal thinking behaviors as well as gestures are very important to take in the context of [**Location (un) 3**] overall level of distress.  It should also be noted that he is quite aware that he has "maladaptive coping" and at times may escalate from 0 to 100 without any clear psychosocial stressors or reasoning.  We have gone over a behavioral approach with safety planning, and we have also encouraged the family to discuss the safety plan with [**Location (un) **] upon discharge in the next week.  This will also give the family language to discuss safety as well as "overwhelming feelings" for [**Location (un) **].  We have given them a handout on behavioral strategies.  We have also gone over a few behavioral strategies which would include creating a "safe place" for [**Location (un) **] to go when he is being disrespectful towards his family or self-deprecating towards himself and has urges of self-injurious behaviors.  We have also discussed deescalation strategies for the parents to use in order to provide some level of role modeling for [**Location (un) **].  We have discussed that when [**Location (un) **] is feeling overwhelmed that his overall organization of feelings and expression of affect, it is very difficult for him to communicate, given that his "prefrontal cortex is being highjacked."  The family clearly understands this and understands that it will require practice on both [**Location (un) **] as well as the family, but they are willing to refine and work through the safety planning as needed.  They are also aware that if they are in a moment of crisis, and they have gone through the safety plan as well as using any deescalation techniques, such as lorazepam sublingually, and they are unable to deescalate the situation to present to [**Hospital 4**] [**Hospital 5**] for additional crisis management.  At this time, [**Location (un) **] does not meet criteria under the Mental Health Act and is safe for discharge.  Please note that he has a history of chronic suicidal ideation and actually does have some coping mechanisms which he can access, including deep breathing, mindfulness techniques, as well as challenging some of his cognitive distortions, which were discussed on this CAPE stay.   2.	Biological.  We have given him a prescription, as noted above, with discharge medications.  The only change that we did make was that his dosing of Prozac should be now in the morning, as nighttime dosing may lead to further agitation and interrupted sleep pattern.  We have discontinued the Seroquel 25 mg p.o. at bedtime, as this is not a very safe choice for a young youth, given the potential metabolic side effects (i.e. weight gain, abnormal fasting blood work).  Instead, we have gone over trazodone as a good alternative to use to help with sleep; however, we still would encourage overall behavioral approaches, such as sleep hygiene as well as higher doses of melatonin ranging from 12 to 15 mg 30 minutes before bedtime.   3.	Psychological interventions:  The bulk majority of our time, in terms of formulating [**Location (un) **] as well as during our discharge interview, was around what psychological avenue would best suit [**Location (un) 3**] needs at this time.  At this time, he is currently seeing [**Signature 1**] , who is part of the high-risk mental health team in [**Location (un) 4**] for the past 2 months.  Although this has been very supportive in nature and quite beneficial for [**Location (un) **] as well as the family to ensure some level of clinical stability, we have discussed that [**Location (un) 3**] needs are likely beyond supportive and insight-oriented therapy.  At this time, he is currently positively engaging in group therapy for anxiety disorders, which we encouraged him to continue, as he is able to feel supported by the community team.  Our social worker, [**Last Name (un) 6**] [**Last Name (un) 7**], has discussed with [**Female First Name (un) 8**] that moving forward, likely a child and youth mental health team approach would be best beneficial.   We have specifically discussed that even though [**Location (un) **] is 13 years of age, that he certainly is displaying maladaptive coping habits or mechanisms in the context of a borderline personality structure.  We specifically have advocated for not only one-to-one therapy around important practices around borderline treatment, but we have also encouraged the family to think about family therapy in the future.  Although it was a tenuous discharge meeting, the family really did understand how complex the borderline personality structure is and that it requires very specific treatment, such as dialectical behavioral therapy.  Although we are not aware of what is available in terms of resources on [**First Name4 (NamePattern1) 4**] [**Last Name (NamePattern1) 9**], we have encouraged the family to continue to advocate around getting services for [**Location (un) **] as well as the family.  For example, working with a therapist specifically around mindfulness techniques as well as regulation responses as well as identifying emotions could be a great starting point for one-to-one therapy for [**Location (un) **].  In addition, mobilizing other supports for the family is essential in this treatment plan, as the family needs to further have a deeper understanding of borderline personality but also work around the behavioral coping mechanisms and support that they need moving forward. 1.	At this time, we do not feel that cognitive behavioral therapy, interpersonal therapy, or mobilizing any manualized type of therapy would be beneficial for [**Location (un) **].  He really requires validation of this hospital stay as well as the strife that he is feeling, even though if it feels "behavioral" to the family.  The family certainly intellectually understands the complexities now of the borderline pathology, especially in the context of adoption, history of attachment which continues with biological mother.  We also feel that the family would benefit from learning more about attachment in the context of having an adopted child and how to manage some of these distressing behaviors, which is clearly affecting not only [**Location (un) **] on an individual basis but the entire family interpersonally.   We would certainly advocate for social work to be involved in this multidisciplinary team approach, as the family would require support and education during the treatment journey of this child.   1.	Social history:  We are in support of him starting his job at McDonald's in the next few months as a way of not only organizing his time but also gaining some level of skills and autonomy.  We also encouraged him to continue with his hobbies, which include music, and potentially to pursue perhaps summer camps that would nurture some of his innate talents as well as abilities.  We also encourage him to lead a healthy lifestyle, which would include not only good sleep hygiene but also a healthy balanced nutrition and 30 minutes of exercise on a daily basis at least 5 times a week.  The social and healthy lifestyle changes can be gradual, and for further information, they can access the [**First Name9 (NamePattern2) 10**] [**Last Name (un) 11**] Mental Health workbook to healthy lifestyles and behaviors. 2.	School accommodations:  [**Last Name (un) 6**] [**Last Name (un) 7**], our CAPE social worker, will be in touch with the school on Monday.  We are aware of the psychoeducation test and some of the learning challenges that [**Location (un) **] is displaying.  From our understanding, he does have a solid IEP in place; however, we would like to further advocate for [**Location (un) 3**] needs, which are likely more emotional, and some of the interpersonal conflict that he may have upon return to school.  We are very aware that he is a bright individual; however, the school stress is absolutely important in order for us to fully formulate some of [**Location (un) 3**] distress outside of the family unit.  In addition, his social abilities and his intense relationship with peers and overall fear of abandonment are very important for the school to understand, as well, moving forward. 3.	Community followup:  We recommend that [**Location (un) **] follows up with his family doctor in the next 2 weeks just to oversee how the medications are going as well as how the family is responding to the community child youth mental health recommendations.  We also have followed up with [**Female First Name (un) 8**], who will coordinate the referral to the Child and Youth Mental Health team in [**Location (un) 4**].  We encouraged the family to contact [**First Name5 (NamePattern1) 6**] [**Last Name (NamePattern1) 7**] in case that there are missing links upon discharge and/or difficulties accessing the child and youth team in [**Location (un) 4**].   4.	Reason for referral in the emergency department:  The emergency physician referred [**Name9 (PRE) **] after 20-tablet ingestion of ibuprofen in the context of an altercation at band camp in Whistler.  This was in the context of him bringing in alcohol, despite knowing the rules, and him reacting to the "consequences."  This was for diagnostic profiling and treatment options. 5.	Status while on the Cape unit:  [**Location (un) **] was admitted for a 24-hour stay in the context of parent-child conflict and increased suicidal ideation.  This was an important admission for not only [**Location (un) **] but as well as the family to clarify the diagnoses that are likely affecting this youth and feeling constantly "invalidated" or dismissed for his mental health concerns.   When [**Location (un) **] was assessed in the emergency department, he had an overall feeling of being overwhelmed and wanting to be in the hospital in order for his parents to "understand what I'm going through finally).  While he was on the CAPE unit, he was very cooperative as well as asking very good questions when they it to diagnosis and his medication changes.   We had given him psychoeducation materials while on the CAPE unit prior to his discharge to look over and to ask us if he requires any additional information around borderline personality disorder.  He agrees that he is quite black-and-white and that he can escalate and that sometimes it probably feels like "walking on eggshells for his parents."  At the same time, [**Location (un) **] was not in the space to receive a lot of information on this stay.  We created it to be a an overall validating experience for him in order to gain some buy in with mental health professionals.  [**Location (un) **] admitted that he felt heard, but it was not until his parents came for the discharge meeting that he clearly escalated.   During that time, 1 hour before the discharge meeting, he called the parents and quickly relayed to staff that he feels overall that his parents "don't care" and that the reason he is in hospital is all "his fault."  We specifically brought this information up during the family meeting to discuss the dissonance of what [**Location (un) **] feels and what he hears or what is communicated to him.  The family then understood that focusing more on [**Location (un) 3**] experience versus discussing the details of "what was said and what was not said" is much more important at this time to ensure that [**Location (un) **] feels heard by his family.   During our discharge meeting, we not only went over the therapeutic plan, but [**First Name5 (NamePattern1) 6**] [**Last Name (NamePattern1) 7**] also went over many different types of behavioral strategies to help the family navigate this type of complex picture.   We also discussed substance use disorders and how although this can be higher in youth that have underlying mental health diagnosis, such as depression, anxiety, or borderline personality, that he has good judgment to know that he is currently using cannabis and alcohol as a means of "maladaptive coping."  He has all of the information intellectually from both his family as well as from the community team.  He does not feel that he has a "substance use problem" at this time, and with the use that he is discussing with us, we felt that he did not require concurrent disorders referral at this time.  In the future, however, if he continues to experiment, or his usage increases in the context of interpersonal stressors, the community team should certainly look at a concurrent disorder referral and potentially use a motivational interviewing modality.   At this time, we are aware that we have shifted the diagnosis for community providers to start thinking of this in a more complex personality structure but also that the symptoms of anxiety, panic attacks, and depressive symptoms are certainly still present cross sectionally.   Thank you for this complex referral.  We hope that the family feels supported and heard upon this discharge; however, we understand that there may be more questions or concerns that come out of this discharge in the next while, and we are happy to either talk to the healthcare professionals as well as the family should they have any immediate concerns.   If you have any questions or concerns, please do not hesitate to contact the undersigned.   [**Signature 12**] Dictated By:  [**Name6 (MD) 13**] [**Name8 (MD) 14**], MD Psychiatry  SN/MODL Job #:  559245 Doc #:  35692913 D:  27/04/2018 17:55:06 T:  27/04/2018 19:33:50


BC MENTAL HEALTH CENTRE AND SUBSTANCE ABUSE	Patient Loc-Svc:  CPE-MH  DISCHARGE SUMMARY  Admitted:	[**2020-03-07**]  (DD/MM/YYYY) Discharged:	[**2020-04-06**]  (DD/MM/YYYY)    This report appears to be incomplete and has been distributed to support continuity of patient care.  If you are the dictating author/preceptor, please make the required corrections/clarification and remove this disclaimer prior to signing the report.  During this dictation, you requested copies of this report to be sent to recipients who could not be properly identified, are not in the provider dictionary, or are prohibited from receiving reports.  While our department will make every effort to distribute copies appropriately, all recipient(s) listed below may not receive a copy.  Dr. [**First Name (STitle) 1**] (sp?)  DATE OF ADMISSION [**2020-08-02**].  DATE OF DISCHARGE [**08-04**]. 2017.  ADMISSION DIAGNOSIS No specific diagnoses is mentioned on the admission note.  DISCHARGE DIAGNOSIS 1.	Alcohol-related neurocognitive disorder. 2.	Rule out FASD.  3.	Rule out oppositional defiant disorder.   4.	Rule out conduct disorder.   5.	Rule out unspecified ADHD. 6.	Rule out learning disorders. 7.	Parent-child relationship problem.  DISCHARGE MEDICATIONS [**Male First Name (un) 2**] was discharged with a prescription for risperidone 0.25 mg p.o. b.i.d. for 30 days.   Of note, on admission, he was on Seroquel 12.5 mg p.o. at bedtime which was discontinued during this admission.  DISCHARGE FOLLOWUP Disposition: [**Male First Name (un) 2**] was discharged to the care of his adopted parents.  During the discharge meeting, we explained in detail that we do not expect that the presentation changed significantly compared to prior to admission although we hope that starting risperidone might help him to better control his behavior.  We highlighted the importance of close followup and better diagnostic assessment through time.  If it is confirmed that he might have a problem related to conduct disorder or severe ODD, the adequate evidence-based management for those disorders need to be implemented and started.   With a diagnosis of alcohol-related neurocognitive disorders or FASD, he is going to receive support from Hollyburn and he has an appointment scheduled for [**08-25**], where he most likely get a behavioral consultant or a behavioral analyst to help him and the family to have a better understanding of the problems and a better handle on them.   Meanwhile, we are going to make a referral to child and youth mental health team so he can get counseling and psychiatry under the same roof.  Until that happens, he will continue seeing Dr. [**First Name (STitle) 1**].  The  parents have stated that cannot afford the private therapy any longer.   We are also going to refer him to [**Signature 3**] so that the urgent mental health team at North Vancouver have some records of his history in case things escalate and parents have to bring him to Lions Gate Hospital so they would be prepared with some prior knowledge about him although we hope that none of those become necessary.   We are also going to request MCFD support file to be open to help the family, either providing respite or a youth worker or an outreach worker as clearly [**Male First Name (un) 4**] escalating problems have affected every family member.   I have strongly suggested and recommended for the parents that until all the services are in place, they should focus on decreasing and minimizing the number of outbursts and volatility in the home.  I suggested that they back off from many of their expectations knowing that in the long run it is not a good idea but short-term because the right and adequate supports are not in place, keeping peace and calm would be the sole objective.  We reviewed the medications safety profile, provided them with Keltie [**Signature 3**] and resources that they can read more about the medication.  I have provided them with the lab requisition to get the basic blood work done so we can establish a baseline in the early days of taking risperidone.  I also advised them that if he continues on this medication, he needs to be referred to metabolic clinic at Children's Hospital.   Finally, we advised them that we cannot foresee the future.  If  emergencies arise, they should not hesitate calling 911 or bringing him to emergency room.  However, most likely by the time that he is seen by mental health or psychiatry in emergency room, the crisis would be over.  If things are not very different than today's presentation, we do not see any benefit in prolonged admission or keeping him longer in the emergency room.  PRESENTATION TO HOSPITAL [**Male First Name (un) 2**] is a 14-year-old male with a complex neurodevelopmental profile and multiple significant attachment disruptions for the first 3 years of his life he has been completely neglected and since 6 years ago has been adopted by his current parents.  However, he continues to suffer from those early attachment injuries.  He has been showing behavioral problems and impulsivity from very young age.  He has been assessed by Sunny Hill and diagnosed with alcohol-related neurocognitive disorders/rule out FASD. The behavior problems are getting worse.  He steals from his parents and stores, sells stuff in school.  They found a Vape in his belongings.  The parents described him running a secret life, not being part of the family, getting angry over little things and escalating to the point of causing real safety risks for other people and it seems to be getting only worse.  He received Seroquel 12.5 mg which he felt is helping, but the parents did not notice any benefit,  recently, he saw Dr. [**First Name (STitle) 1**] who suggested risperidone, but because he did not do the blood work, parents did not give him the medication.  He got admitted due to escalating behavioral problems after a visit to the dentist's office and stealing something from that office which he denies although it was found in his pocket.  He was admitted to CAPE and he started risperidone which he is tolerating well.  HOSPITAL COURSE During this short hospitalization, he slept well overnight, did not show any behavioral problems.  [**Name (NI) 5**] took medication without any side effects.  He did not voice any suicidal ideation, self-harming urge, or threat or plan to harm anyone else.  During the family meeting/discharge meeting, he sat  silent for the most part, said that overall he agrees with his parents' assessment, but could not offer any insight why he is doing or engaging in those problem[**Name (NI) 6**] behaviors.  BEHAVIORAL OBSERVATION/MENTAL STATUS EXAM AT DISCHARGE [**Male First Name (un) 2**] appears as stated age, fairly groomed and [**Last Name (un) 7**], in casual clothes.  Good eye contact.  No psychomotor activation or retardation.  Friendly and cooperative.  Speech is normal rate, rhythm volume. Mood reports is slightly downcast.  Affect full, euthymic, reactive.  Thought process linear and organized.  Thought content denies any suicidal ideation.  No homicidal ideation.  No auditory or visual hallucinations.  Insight and judgment both poor.   DICTATION ENDS HERE   [**Signature 8**] Dictated By:  [**First Name4 (NamePattern1) 9**] [**Last Name (NamePattern1) 10**], MD Psychiatry  AE/MODL Job #:  116760 Doc #:  33100218 D:  [**2020-04-06**] 21:48:52 T:  07/11/2017 22:58:28


russell body duodenitis ( rbd ) is a rare inflammatory disease characterized by an abundance of polyclonal plasma cells present in the duodenal mucosa .
these plasma cells contain intracytoplasmic eosinophilic globules of condensed immunoglobulin , the so - called russell body .
we describe the case of a patient with rbd in whom endoscopic and histopathologic findings were observed chronologically , along with a review of the relevant literature .
he was found to have a nodule in the right middle lung field on a plain chest radiograph at a local clinic , and was referred to our hospital for detailed examination .
a nodule measuring 2 cm was detected in segment 8 of the right lung on chest plain computed tomography ( ct ) .
the morphology of the nodule was lobulated , and cavitation was observed in the interior .
results of smear , culture , and polymerase chain reaction assay from sputum specimens were all negative for tuberculosis .
bronchoscopy was performed on hospital day 9 , during which bronchial lavage fluid was collected , and a biopsy of the nodule was performed .
double capsule - like circular objects were positive for periodic acid - schiff stain and grocott stain , yielding a diagnosis of pulmonary cryptococcosis .
moreover , the level of the cluster of differentiation ( cd ) 4 was 570/l , the cd8 level was 655/l , and the cd4/cd8 ratio was 0.87 , suggesting no evidence of aids . on hospital
esophagogastroduodenoscopy ( egd ; day 14 ) revealed a significant amount of residue and an irregular ulceration with surrounding elevation of the duodenal bulb ( fig .
1a ) , which had brought about severe stenosis . with the suspicion of duodenal cancer , biopsy samples were obtained from ulcer edges .
although admixed with various inflammatory cells , necrotic tissues were observed , but no definition of adenocarcinoma cells was found ( fig .
however , since some large atypical cells were admixed with infiltrating inflammatory cells , reexamination was required to rule out undifferentiated carcinoma and malignant lymphoma .
the second egd ( day 21 ) and the third egd ( day 30 ) revealed no signs of ulcer healing .
contrast - enhanced upper gastrointestinal radiography ( day 37 ) revealed severe stenosis from the duodenal bulb to the superior duodenal angle ( fig .
2 ) . positron emission tomography - ct was performed to screen the whole body for malignant tumors .
no significant accumulation of fluorodeoxyglucose was observed in any site except the lesion of pulmonary cryptococcosis in the right lung , and no accumulation was detected in the duodenal bulb .
considering this benign stenosis , we performed a gastrojejunostomy ( day 43 ) , and thereafter , oral intake became possible .
the fourth egd ( day 56 ) revealed that the peripheral redness and edema of the ulcers had become more severe than in the previous findings ( fig .
biopsy samples revealed dissemination of large cells with eosinophilic cytoplasms and eccentric nuclei in the necrotic / granulation tissue of the duodenal lamina propria ( fig .
3b ) . the large cells were cd20( ) , cd68( ) , cd79a(+ ) , and s100( ) , and they were  chain(+ ) or  chain(+ ) , suggesting russell bodies derived from polyclonal plasma cells ( fig .
the fifth egd ( day 91 ) revealed that the ulcers in the duodenal bulb had reduced in size , and some scarring was present ( fig .
although a biopsy at this time confirmed the presence of a few russell bodies , the majority had disappeared ( fig .
the patient is being followed up while continuing the oral administration of a proton pump inhibitor ( ppi ) .
hsu et al .   showed that russell bodies originate from distended rough endoplasmic reticulum in which immunoglobulin is inhibited from being secreted and condensed .
tazawa and tsutsumi   first reported russell body gastritis ( rbg ) in 1998 , in which russell bodies were found in many plasma cells infiltrating the gastric mucosa .
first reported in a patient positive for hiv ; only five cases have since been reported [ 5 - 8 ] .
the differential diagnoses include plasmacytoma , mucosa - associated lymphoid tissue lymphoma , and signet ring cell carcinoma . in the present case , because the russell bodies were derived from plasma cells positive for cd79a and were suggested to be polyclonal by the mixture of  and  chain - positive cells , rbd was diagnosed .
many patients with rbg are positive for h. pylori , which is believed to be associated with the development of rbg .
however , only one of the five previously reported cases of rbd was positive for h. pylori .
the other background diseases were hiv infection in one , crohn disease in one , retroperitoneal metastasis of ureteral cancer in one , and adenocarcinoma of the ascending colon in one case .
although the development of russell bodies is assumed to be associated with chronic inflammation , microorganisms , and immunodeficiency , the causes of their development remain unknown .
although russell bodies are frequently found in benign tissue adjacent to a malignant tumor , there are also reports suggesting that the production of chemokines in tumor cells is associated with the development of russell bodies . in the present case ,
the patient was negative for h. pylori and hiv , and there was no evidence of malignancy or immunodeficiency .
we could chronologically observe the endoscopic appearance and histopathological findings of rbd in our patient .
when the ulcers were first detected , although severe infiltration of inflammatory cells was observed , rbd was not manifested . through the aggravation of the ulcers
furthermore , the fifth egd revealed a tendency for the ulcers to heal , and the majority of the russell bodies had disappeared . from these processes , it was assumed that the russell bodies were not a cause of the ulcerations , but byproducts secondarily induced by a severe inflammatory state after the development of the ulcers . in the present case , because food residues were always retained in the duodenal bulb , mechanical stimulation might also have been associated with the development of the russell bodies .
regarding therapeutic responses of russell bodies , there is a report of patients with rbg who were positive for h. pylori , in whom the endoscopic findings improved after h. pylori eradication and the russell bodies disappeared .
the present patient was negative for h. pylori and had not undergone h. pylori eradication .
his treatment consisted of administration of a ppi and gastrojejunostomy , which are assumed to have contributed to the resolution of the local inflammation . as for the correlation with the degrees of inflammation at the ulcer site
, the russell bodies would be expected to appear and disappear as the degree of inflammation changed .
the prognosis was favorable with the internal use of a ppi in cases of rbg negative for h. pylori .
there have been no published reports of recurrence or malignant transformation during follow - up .
however , it is often difficult to distinguish russell bodies from plasmacytoma , mucosa - associated lymphoid tissue lymphoma , and signet ring cell carcinoma .
multiple endoscopic observations and biopsies , like that used in the present case , are required to diagnose malignant disease .
this was a valuable case in which the clinical and pathological features of rbd , an extremely rare disease , could be compared in the present patient from onset to healing .

 a 64-year - old man was found to have a nodule in his right lung .
 he also complained of nausea and abdominal pain during the clinical course .
 esophagogastroduodenoscopy revealed a duodenal ulcer associated with severe stenosis and a suspicion of malignancy .
 however , three subsequent biopsies revealed no evidence of malignancy .
 the fourth biopsy showed scattered large eosinophilic cells with an eccentric nucleus , leading to a diagnosis of russell body duodenitis ( rbd ) .
 rbd is an extremely rare disease , and little is known about its etiology and clinical course .
 the pathogenesis of rbd is discussed based on our experience with this case .


microglia - mediated neuroinflammation and t cell infiltration constitute major hallmarks for neurodegeneration , yet the molecular and cellular crosstalk between microglia and t cells is poorly understood .
lipopolysaccharide ( lps ) from rhodobacter sphaeroides ( lps - rs ) is a potent tlr4 antagonist in both human and murine cells and prevents tlr4 mediated inflammation .
lps - rs is a penta - acylated lipid a and utilizes two distinct mechanisms to block lps / tlr4 signaling .
the mechanism involves direct competition between underacylated lipid a and hexa - acylated lipid a for binding on md-2 , whereas another mechanism implies the ability of penta - acylated lipid a : md-2 complexes to inhibit hexa - acylated endotoxin : md-2 complexes and tlr4 functions [ 25 ] .
a critical question is asked whether lps - rs can be employed to fine - tune the major hallmarks of microglia - mediated inflammation , phagocytosis , and t cell activation . in resting state , microglia performs maintenance and immune surveillance but activation either by injury or immune stimuli triggers neuroinflammation resulting in neurotoxicity .
microglia expressed toll - like receptors ( tlrs ) trigger or resolve inflammation and injury and tlr4 is reported to exacerbate microglial activation , neuroinflammation , and lymphocyte infiltration resulting in neurodegeneration [ 7 , 8 ] .
tlr4 functions as receptor for bacterial lipopolysaccharide ( lps ) and other endogenous molecules like hsp 70 , hsp60 , amyloid beta , -synuclein , and so forth . in the study
, lps is taken as an exemplary ligand for tlr4 to elucidate immune regulation at molecular and cellular levels .
involvement of the receptor is known in alzheimer 's disease ( ad ) and parkinson 's disease ( pd ) [ 10 , 11 ] and deficiency protects mice against neurodegeneration following injury [ 12 , 13 ] .
receptor ligation on antigen presenting cells including microglia would present the processed antigen to the cells of adaptive immune response including the t cells .
the microenvironment generated during the course of antigen presentation and inflammation dictates the outcome of  t cell response .
the event leads to the priming and recruitment of  t cells through a series of coordinated events .
the infiltrating t cells can critically influence the outcome of neurodegeneration that is either resolving it and/or exacerbating it through microglia activation and/or suppression .
the inflammatory subset of  t cells including th1 and th17 strongly contributes to chronic neuroinflammation , perpetuating neurodegenerative processes , whereas the immunosuppressive tregs decrease inflammatory functions with neurosupportive microenvironment .
realizing the fact that t cell response can govern the fate of neurodegeneration progression or resolution , in this regard , the fate of  t cell subset differentiation by lps - rs was explicated in detail .
bv2 microglia is used as an in vitro model to dissect molecular mechanism of lps - rs mediated tlr4 antagonism .
lps - rs has been reported to be nontoxic in rodents [ 4 , 17 ] .
the study gains insight into the mechanisms of lps - rs mediated regulation of signaling pathways , prevention of neuroinflammation , and subsequent decrease of neuronal loss following aberrant apoptosis and phagocytosis .
anirban basu , nbrc , india and mouse neuro2a cell line obtained from national centre for cell science ( nccs ) , pune , india were used .
the cell lines were maintained in dmem , 10% heat inactivated fetal bovine serum ( fbs ) , and supplements under appropriate conditions .
for the experiments , cells were washed twice and pretreated with ultrapure lps - rs ( invivogen ) , sb202190-p38 mapk inhibitor ( 10  m ) , pd184352-erk1/2 inhibitor ( 5  m ) , sp600125-jnk inhibitor ( 10  m ) , and curcumin - nf-b signaling inhibitor ( 10  m ) ( all from sigma - aldrich ) in 1% fbs containing dmem for 2  hrs followed by lps - tlr4 ligand ( 1  g / ml ) ( sigma - aldrich ) .
total rna was extracted and quantified and 1  g of total rna was used for cdna synthesis .
the cdna for indicated genes were amplified using gene specific primers ( see supplementary table 1 in supplementary material available online at http://dx.doi.org/10.1155/2015/361326 ) under following conditions : 95c for 5  min , 95c for 30 seconds , annealing at 5560c for 45 seconds , and 72c for 1 minute for a total of 2030 cycles ( for different genes ) followed by final extension at 72c for 10 minute and each sample was amplified for -actin to ensure equal cdna input . expression and phosphorylation of the proteins were assayed by western blot as described   using specific primary antibodies : rabbit anti - tlr4 , mouse anti - phospho - p38 , rabbit anti - phospho - erk1/2 , rabbit anti - phospho - jnk1/2 , rabbit anti - p38 , rabbit anti - erk1/2 , mouse anti - jnk1/2 , mouse anti - p - nf-b , rabbit anti - bax , rabbit anti - bcl2 , and mouse anti--actin at 1  :  1000 dilution .
the nitrite production was examined using griess reagent ( sigma - aldrich ) as described previously .
cell viability was measured using mtt assay ( sigma - aldrich ) as per manufacturer 's guidelines .
briefly , neuro2a cells were plated and  differentiated  on coverslips as previously described .
bv2 microglia cells were plated simultaneously in 24-well culture plates and pretreated with lps - rs ( 5  g / ml ) and then stimulated with lps ( 1  g / ml ) for 48  hrs .
then , the neuron - containing coverslips ( cell - side down ) were moved into the microglia - seeded well , allowing neurons and microglia to share the same culture media , but without direct cell - cell contact ( using three equally spaced small paraffin feet ) . the coverslips were moved out and neuronal viability was assessed using mtt assay .
morphologic examination of neurons was done under inverted phase - contrast microscope ( olympus ) .
briefly , bv2 cells were grown for 24  hrs and then treated as indicated followed by 1  g / ml lps treatment for 60  min .
after washing , cells were fixed with 1% paraformaldehyde for 5  min at room temperature and then permeabilized with pbst ( pbs containing 0.2% triton x-100 ) . after blocking in the blocking buffer ( 2% bsa in pbst ) for 2  hrs the cells
were sequentially incubated with mouse anti - nf-b p65 antibody ( invitrogen ) and secondary antibody anti - mouse igg ( alexa fluor 488 ) .
4,6-diamidino-2-phenylindole ( dapi 1  g / ml ) was used to visualize nucleus and cells were examined under fluorescence microscope ( olympus ) .
measurement of intracellular e. coli dh5 was used to determine the phagocytosis ability as described .
briefly , bv2 cells were pretreated with lps - rs or cyto - d for 2  hrs followed by lps treatment for 24  hrs .
cells were washed twice and infected with e. coli for 30 minutes and the extracellular bacteria were washed and killed with gentamicin ( 100  g / ml ) .
the cells were washed , lysed , and plated overnight on luria - bertani agar and colony forming unit ( cfu ) was calculated . in parallel experiment ,
phagocytic activity was evaluated by fluorescence microscopy . in brief , for staining of e. coli dh5 with dapi , the e. coli dh5 were incubated with dapi ( 1  g / ml ) for 5  min and extracellular dapi was removed by 4 times washing at 12,000  g for 3  min at 25c . then microglial cells were infected with dapi stained e. coli dh5 for 30  min followed by three washes with pbs and phagocytosis was evaluated by fluorescence microscopy at 40x magnification .
we examined the role of tlr4 in microglia - mediated neuroinflammation and neuronal cell death .
briefly , bv2 microglia were transfected under serum - free conditions with tlr4 sirna or control sirna ( 1  g / ml ) .
tlr4 sirna sequence ( sense 5-gga acu ugg aaa agu uug-3 ) and control sirna ( sense 5-gug cac aug agu gag au uu-3 ) in psilencer 4.1-cmv neo sirna expression vector were used as described previously   and transfected using lipofectamine 2000 ( invitrogen ) , according to the manufacturer 's instructions . after overnight incubation
the medium was replaced and the cultures were continued for 48  hrs before the assays were performed .
the experiments of splenocytes from c57bl/6 mice were performed as per the guidelines and protocol approval by committee for the purpose of control and supervision of experiments on animals ( cpcsea ) .
rbc depleted splenocytes were pretreated either with or without lps - rs followed by lps treatment for 72  hrs .
the cells were then analysed for proliferation using mtt assay , treg population using flow cytometry , and cytokines using elisa . for rt - pcr
cd4 t cells were isolated following negative selection using streptavidin - imag beads . to confirm the immunosuppressive function of treg cells , cd4 t cells were treated with recombinant ( r ) il-2 in presence or absence of ril-10 and the supernatants
were used for pretreatment of microglia followed by stimulation with lps , and the inflammatory function of microglia was determined by measurement of tnf- and no .
mouse regulatory t cell staining kit was used for staining as per the manufacturer 's instructions ( ebioscience ) .
cd4cd25 cells were gated and the expression of treg specific marker foxp3 was determined using cellquest software .
cytokines in the culture supernatants were detected using elisa for the indicated cytokines as per manufacturer 's guideline ( ebioscience ) .
each individual experiment was repeated a minimum of three times and the statistical significance of differences between groups was determined by one - way anova followed by tukey 's post hoc multiple comparison tests .
the data were expressed as mean  sem from three independent experiments . a statistical p value less than 0.05 ( p  0.05 ) was considered significant ( p  0.05 versus untreated control and p  0.05 versus cells treated with lps ) .
we investigated the effect of lps - rs mediated regulation of lps induced microglia activation , expression of tlr4 , and inflammatory cytokines .
bv2 microglial cells were pretreated with lps - rs ( 0.55  g / ml ) for 2  hrs followed by treatment with lps ( 1  g / ml ) and expression of tlr4 was analyzed by rt - pcr ( 6  hrs ) ( figure 1(a ) ) and tlr4 western blot ( 24  hrs ) ( figure 1(b ) ) .
the concentrations of lps - rs used did not induce cytotoxicity and no and tnf- production ( figures 1(c ) and 1(d ) ) .
lps - rs significantly decreased tlr4 induced cytokines tnf- , il-1 , and il-6 ( figure 1(e ) ) and inflammatory genes inos and cox-2 ( figure 1(f ) ) accompanied with decreased no and tnf- production ( figures 1(g ) and 1(h ) ) .
microglial morphology data provides evidence that lps - rs ameliorate microglia activation as ramified morphology was regained ( supplemental figures s1a , s1b , and s1c ) .
these data indicate that lps - rs exhibited a broad spectrum of inhibitory effects on microglia activation and production of inflammatory mediators .
nf-b phosphorylation and nuclear translocation are important events that trigger transcription of inflammatory genes [ 18 , 24 ] .
lps - rs significantly inhibited lps induced phosphorylation and nuclear translocation of p-65 nf-b in a dose dependent manner ( figures 2(a ) and 2(b ) and supplemental figure s2 ) .
mapks , playing an important role in the microglia activation and inflammation , are considered potential targets for treatment of neuroinflammatory diseases [ 18 , 20 , 2527 ] .
we examined the regulatory effects of lps - rs on mapk pathways in dose and time dependent manner .
lps - rs inhibits lps - induced phosphorylation of jnk 1/2 and p38 mapks but left erk 1/2 unaltered ( figures 2(c ) and 2(d ) ) .
consequent to the above observations , the essentiality of these pathways was determined using inhibitors and the nf-b and jnk1/2 were found to be indispensable for lps induced no and tnf- secretion ( figures 2(e ) and 2(f ) ) .
collectively , the results suggest that lps - rs prevents neuroinflammation through negative regulation of nf-b and/or mapks .
it is well documented that activated microglia significantly contributes neuronal apoptosis and subsequent clearance [ 10 , 28 ] .
aberrant activation of microglia initiates a series of inflammatory cascades that leads to deregulated apoptosis . in neuro2a - bv2 microglia coculture ,
lps activated microglia induces neuronal cell death which was inhibited significantly by lps - rs ( figures 3(a ) and 3(b ) ) .
lps - rs , did not induce neuronal cell death in the differentiated neuro2a cells ( data not shown ) .
lps activated microglia - induced abnormal neuronal morphology together with fragmentation of neurites and shrunken cell bodies , which were significantly inhibited by lps - rs affirming its neuroprotective functions ( figure 3(c ) ) including neurite length and cell perimeter ( figures 3(d ) and 3(e ) ) .
the effect of lps - rs on the intrinsic apoptotic pathway was investigated by determination of the bax  :  bcl-2 ratio .
exposure of differentiated neuro2a cells to supernatant from differentially treated microglia accounted for threefold decrease in the ratio that was significantly high during lps treatment ( figure 3(f ) ) suggesting inhibition of apoptotic cell death . to examine and confirm the functional role of tlr4 in microglia - mediated neurotoxicity
, the expression was silenced using sirna and expression level confirms silencing ( figure 3(g ) ) .
tlr4 silencing attributes to decreased production of inflammatory mediators tnf- and no after lps treatment ( supplemental figure s4 )
. exposure of differentiated neuro2a cells to the supernatant from control sirna and tlr4 sirna transfected lps stimulated microglia showed increased neuronal cell death in the control while the effect was significantly inhibited in tlr4 sirna transfectants .
cell viability : tlr4 sirna + lps : 75%   3.5 , control sirna + lps : 30%   3 , p < 0.005 ( figure 3(h ) ) . to extrapolate our findings with an in vitro model of ad
, we confirmed the potential role of lps - rs in rescuing  amyloid induced neuroinflammation and neuronal loss ( supplemental figure s5 ) .
collectively , lps - rs and/or tlr4 silencing inhibits lps induced microglia - mediated neuronal apoptosis via inhibition of inflammation in the neuro2a - bv2 microglia coculture system .
microglia plays crucial role in phagocytosis of apoptotic or dead neurons , studies have demonstrated that the mechanisms involve either eat - me signal on the target cell or coreceptor on the microglia cell surface .
modulation of phagocytosis is important to prevent neurodegenerative processes ; hence , we examined whether phagocytic activity of microglia can be regulated by lps - rs .
unstimulated cells ingested low number of bacteria ( 10  10  cfu / ml ) while lps activated microglia ingested highest number of bacteria ( 80  10  cfu / ml ; p < 0.0002 ) .
microglia pretreated with lps - rs phagocytosed significantly less number of bacteria ( 25  10  cfu / ml ; p < 0.0002 ) and the phagocytic inhibitor cytochalasin d pretreatment acted as a positive control with least number of ingested bacteria ( 8  10  cfu / ml ; p < 0.0002 ) ( figure 4(a ) ) .
microscopic analysis of labeled bacteria confirms the inhibitory potential of lps - rs for phagocytosis which is otherwise aberrantly activated upon tlr4 activation ( figure 4(b ) ) .
the data indicates that lps - rs inhibits lps induced microglial phagocytic activity that may serve as a key and sole strategy to prevent neurodegeneration .
appropriate antigen processing and presentation are the key governing factors that orchestrate the t cell response . during the neuroinflammatory burden the t cells are biased to be activated , aggravating the problem .
the governing factors deciding the fate of t cell differentiation are expression of costimulatory molecules and chemokine receptors accompanied with release of cytokines : the releases of chemoattractants , chemokines , and guide t cells infiltration to the site of injury / infection .
lps induced elevated levels of the key costimulatory molecules and activation markers cd80 , cd86 , and cd40 were negatively regulated upon pretreatment with lps - rs ( figure 5(a ) ) .
lps - rs however did not show significant modulation in the expression of mhc - ii gene .
researchers have highlighted the fact that tlr4 is indispensable for leukocyte recruitment into brain in response to lps   and upregulated expression of ccr5 in neurological diseases is often immunolocalized in microglia .
we report similar observation that lps stimulation results in significantly elevated expression of ccr5 which was downregulated by lps - rs .
the chemokines , including mip-1 and ccl5 , are the major activator and chemoattractants for monocytes and t cells   and were significantly inhibited by lps - rs ( figure 5(b ) ) .
our finding indicates that lps - rs mediate inhibition of gene expression of these costimulatory molecules , chemokines , and chemokines receptor which may govern microglia - t cell interaction and t cell infiltration into the brain .
the activation state ( activated or tolerogenic ) of the antigen presenting cells and subsequent events dictate adaptive immune functions .
tolerogenic apcs can be potential target to design and direct effective strategy to regulate inflammatory and pathogenic t cells .
we have tried to understand the activating / tolerogenic effect of lps - rs in splenocyte cultures that may regulate the t cell outcome .
lps - rs resulted in approximately 3-fold lesser proliferation as compared to the cells activated by lps ( figure 6(a ) ) . to further correlate reduced proliferation with functional markers for the t cells ,
lps remarkably induced transcription factors and cytokines for th1 ( tbet and ifn- ) and th17 ( ror- and il-17 ) cells .
interestingly , pretreatment with lps - rs demonstrated that t cells differentiated to treg lineage as evidenced by its signature transcription factor and cytokines ( foxp3 , tgf- , and il-10 ) ( figures 6(b)6(f ) ) . to confirm the phenotype , the cells from parallel experiment were analysed for treg surface marker ( foxp3 ) using flow cytometry .
lps - rs pretreatment significantly enhanced foxp3 expression ( 40% ) on cd4cd25 gated cells as compared to lps stimulation alone ( figure 6(g ) ) .
the generation of t regulatory cells during lps - rs pretreatment can be a possible reason for reduced proliferation [ 33 , 34 ] .
taken together , the data suggest that lps treatment directs th1/th17 differentiation while pretreatment with lps - rs confers induction of tregs cells .
t regulatory cells are known to potent suppressors of the adaptive immune system and also modulate innate immune cells through induction of alternative activation of macrophages .
studies have shown that foxp3cd4 treg cells play crucial role in maintenance of immunological homeostasis and tolerance in t lymphocytes and macrophages .
several studies have shown that alternative ( anti - inflammatory / tolerogenic ) activation of microglia is a beneficial response to cns injury [ 36 , 37 ] .
cellular factors influencing microglial fate include cns infiltrating t cells amongst others . infiltrating cd4 t - cells participate and influence microglial activation and consequent neuronal damage .
microglia may acquire inflammatory neurotoxic phenotype or immunosuppressive neurosupportive phenotype [ 15 , 38 ] . to examine
whether immunosuppressive and/or tolerogenic potential of treg cells manipulate activation state of microglia , we used anti - cd3/cd28 stimulated cd4 t cells and treated them in presence or absence of ril-10 along with ril-2 .
the cells treated with ril-2 in absence of ril-10 showed enhanced proliferation and absence of treg phenotype while the cell treated with r - il-2 in presence of ril-10 demonstrated reduced t cell proliferation and expressed treg marker ( foxp3 ) ( data not shown ) . the supernatants from the experiment were collected and were used to pretreat microglia followed by lps stimulation .
the supernatant from ril-10 induced treg cells significantly decreased secretion of no and tnf- from microglia as compared to control ( figures 7(a ) and 7(b ) ) .
the results indicate that ril-10 induced treg cells negatively regulate inflammatory function of microglia and render them to gain immunosuppressive or tolerogenic functions .
in brain pathology , inflammation causes bystander injury that is typically irreversible followed by sustained neuronal and cognitive function loss .
the cns exhibits tlrs , including tlr4 , has predominant expression on microglia , and initiates typical response to cns infection or injury [ 10 , 12 , 28 , 39 ] .
however , in some cases activation of microglia contributes to neurodegeneration by releasing inflammatory and cytotoxic factors , including nitric oxide and tnf- as in ad and pd [ 18 , 40 ] .
reports highlight the fact that upregulated tlr4 initiates inflammation and increases phagocytic activity of microglia followed by neuronal loss in ad and pd [ 10 , 12 , 39 ] .
tlr4 deficiency protects mice against neurodegeneration and showed increased survival of neurons confirming the involvement of the receptor .
mutation in the receptor decreases microglial activation and preserves cognitive functions in mouse model of ad .
thus , tlr4 activation is the major culprit for microglia - mediated neuronal loss as demonstrated by many leading groups . in the same context
, our study using a tlr4 antagonist , lps - rs , reveals that lps - rs markedly inhibits tlr4 expression with substantial and subsequent decrease of inflammatory mediators including il-1 , tnf- , il-6 , inos , and cox-2 .
our findings are supported by studies that highlighted the deficiency and mutation in tlr4 benefits in preserving cognitive functions and better neuronal well - being [ 13 , 14 ] .
elevated activation of nf-b and mapks is directly involved in pathogenic events of ad and pd [ 18 , 20 , 2427 , 41 ] .
nf-b exists in the cytosol as a dimer of p-65 nf-b and ib , an associated inhibitory protein . upon activation the phosphorylated p-65 nf-b translocates to the nucleus inducing a cascade of inflammatory genes [ 42 , 43 ] .
in addition to nf-b , mapks , playing an important role in the microglia activation and secretion of inflammatory mediators , are considered potential targets for treatment of neuroinflammatory diseases [ 26 , 27 ] . in this
regard , our findings indicate that lps - rs significantly blocks lps induced phosphorylation of mapks and nf-b p65 .
thus , lps - rs can be exploited as possible mechanisms for better treatment regimes .
activated microglia through inflammation influences neuronal apoptosis and progression of neurodegenerative diseases [ 6 , 12 , 28 , 44 ] . using neuro2a - bv2 microglia coculture
we report that lps induced microglial neurotoxicity was significantly inhibited by lps - rs and the protective effects might be due to its inhibitory action on aberrant neurotoxic activation . pretreatment with lps - rs
neuro2a cells exposed to supernatant from lps activated microglia resulting in better neuronal survival . to confirm the role of tlr4 in microglial activation and neurodegenerative processes
silencing of tlr4 was sufficient to confirm its role in inflammatory neuronal loss and was confirmed with  amyloid as well .
our findings are consistent with the evidence that reports neuroprotective effects of tlr4 antagonism in spinal cord and mouse model of neurodegeneration .
we have exemplified with a strong background that lps - rs is a potential candidate to recover tlr4 mediated neuronal damage .
damaged , dead , or dying neurons are phagocytosed by microglia to maintain homeostasis in the cns but aberrantly activated microglia fails to discriminate between live and damaged / dead neurons , resulting in phagocytic removal of live neurons , contributing to significant neurodegeneration [ 8 , 18 , 44 ] .
recent study has shown that loss of neurons during inflammation , executed by microglial phagocytosis and its inhibition , is sufficient to prevent inflammatory neuronal death . in this regard
, we have explored the potential of lps - rs as phagocytic inhibitor and demonstrate that it significantly blocks phagocytosis of e. coli dh5 in lps activated microglia , as analysed by fluorescent microscopy and cfu of ingested e. coli dh5. the results provide a novel mechanism of lps - rs antagonism which has never been explored earlier and may provide excellent therapeutic strategy .
furthermore , cns infection and/or injury initiates leukocyte trafficking in the brain that has earlier been reported to worsen disease outcome . however , there are still discrepancies in the reports [ 15 , 31 , 46 , 47 ] .
the cd4cd25 regulatory t cells have neuroprotective activities through regulation of microglia activation and t cell functions by secreting immunosuppressive cytokines [ 48 , 49 ] . in this regard our data
we demonstrate that tlr4 antagonism by lps - rs not only rescues microglia - mediated inflammatory events but also results in treg induction , and the findings are also supported by other studies . naturally occurring treg cells express foxp3 , the key regulator of treg cell development and function ; studies using treg
therefore , t reg cells can mediate their actions by attenuating inflammatory responses , thus ameliorating neuronal degeneration , yet the exact mechanism of their actions in the injured cns is poorly understood . to provide a better understanding in this context , using the conditioned cytokines we have shown that tregs can transfer their tolerogenic functions to microglia as evidenced by decreased tnf- and no production .
our data strongly recommend that tlr4 antagonism can be a strategy providing neuroprotection through regulation of microglia as well as the t cells .
conclusively , the study reports that lps - rs prevents tlr4 induced neuroinflammation and microglia activation via negative regulation of nf-b and mapks signaling pathways conferring decreased neuronal apoptosis and subsequent phagocytosis by the microglia .
lps - rs through tlr4 antagonism not only regulates microglial function but also may serve to induce treg cells that support the tolerogenic microenvironment and further strategies may be designed and implemented not only for cns diseases but also for other disease regimens .

 microglia activation and neuroinflammation are key events during the progression of neurodegenerative disorders .
 microglia exhibits toll - like receptors ( tlrs ) , with predominant expression of tlr4 , inducing aberrant neuroinflammation and exacerbated neurotoxicity .
 studies suggest that microglia initiate infiltration of t cells into the brain that critically influence disease conditions .
 we report that lps - rs , through tlr4 antagonism , significantly inhibit tlr4 mediated inflammatory molecules like il-1 , il-6 , tnf- , cox-2 , inos , and no .
 lps - rs regulates jnk / p38 mapks and p65-nf-b signaling pathways , which we report as indispensible for lps induced neuroinflammation .
 lps - rs mitigates microglial phagocytic activity and we are first to report regulatory role of lps - rs which blocked microglia mediated inflammation and apoptotic cell death .
 lps - rs significantly inhibits expression of costimulatory molecules cd80 , cd86 , and cd40 .
 chemokine receptor , ccr5 , and t cell recruitment chemokines , mip-1 and ccl5 , were negatively regulated by lps - rs .
 furthermore , lps - rs significantly inhibited lymphocyte proliferation with skewed regulatory t ( treg ) cell response as evidenced by increased foxp3 , il-10 , and tgf-. additionally , lps - rs serves to induce coordinated immunosuppressive response and confer tolerogenic potential to activated microglia extending neurosupportive microenvironment .
 tlr4 antagonism can be a strategy providing neuroprotection through regulation of microglia as well as the t cells .


the prostate - specific antigen ( psa ) level has been an important diagnostic tool for detecting prostate cancer .
it has been shown that an abnormal digital rectal examination ( dre ) has markedly decreased and biochemical findings ( elevated psa ) have increased over the past 20 years for the indication of prostate biopsy .
this means that evaluation of prostate cancer is more and more based on the psa level rather than on suspicious dre
. however , cancer detection rates from biopsy in the presence of isolated psa elevation and a normal dre range between 30% and 40% . also , a high concentration of psa can be found in benign disorders such as benign prostatic hyperplasia ( bph ) , urinary tract infections , and bacterial prostatitis [ 2 - 5 ] .
although it has been reported that acute inflammation is necessary to cause psa elevation , there is growing evidence that subclinical inflammation may also contribute to rises in psa levels [ 6 - 9 ] .
furthermore , several investigators have shown that treatment of chronic prostatitis , when identified , can decrease psa , which suggests that the use of anti - microbial or anti - inflammatory drugs may reduce the number of men who need prostate biopsies .
there is no doubt that symptomatic prostatitis needs to be treated , but uncertainty exists about the appropriate management of asymptomatic patients with elevated psa and normal dre .
the aim of our study was to investigate the possibility of reducing the number of prostate biopsies in patients with a high psa level showing a psa decrease or normalization after antibiotic therapy .
this approach could be useful in patients for whom it is necessary to postpone biopsy and in patients with previous negative biopsies who are willing to avoid biopsy until further psa increase .
this investigation was conducted prospectively among 413 patients with a serum psa level of over 4 ng / ml to under 10 ng / ml from january 2004 to december 2009 .
subjects were excluded if they had been treated by 5-alpha reductase inhibitor for more than 3 months or if they had a history of transurethral resection of the prostate .
the psa level was determined by using immunoenzymatic assay before dre and transrectal ultrasonography ( trus ) to avoid false - positive results . to exclude prostatitis
, all patients underwent the expressed prostatic secretion ( eps ) or voided bladder urine 3 ( vb3 ) test to be classified into two groups .
one group had positive findings on the eps or vb3 test and the other group had negative findings .
a cover slip was placed over the specimen and it was examined under high - power microscopy . a positive finding
was defined as a white blood cell ( wbc ) count higher than 10 in the prostate secretion after eps or wbc higher than 10 in vb3 urine after eps .
the patients with a positive result were treated with quinolone antibiotics for 2 months , and they were asked to return for repeat screening 2 months later . if the psa level was still higher than 4 ng / ml after 2 months , the patients underwent prostate biopsy . in the other cases , the patients avoided prostate biopsy
the subjects underwent at least 10 core biopsies with transrectal ultrasound - guided needle biopsy of the prostate .
chicago , il , usa ) was used for the statistical analysis , and independent t - tests were used for analysis of the characteristics of both groups .
of the 413 men studied , 215 ( 52% ) patients had positive findings on the eps or vb3 test .
of the 215 patients , 53 men avoided prostate biopsy because their serum psa level had decreased to less than 4 ng / ml . the other patients ( 162 of 215 ) still had an elevated serum psa level of more than 4 ng / ml , including 7 in whom the biopsy results revealed cancer .
patients with negative findings on the eps or vb3 test ( 198 of 413 ) underwent prostate biopsy immediately ( fig .
the total prostate cancer detection rate was 11.6% in our subjects , whereas it was 20.7% in the patients with negative findings on the eps or vb3 test and 3.3% in those with positive findings , respectively .
the mean age was significantly different between the positive group ( 65.0 ) and the negative group ( 71.2 ) .
there were no significant differences in the mean initial serum psa level or prostate volume between the groups ( table 1 ) .
since psa was introduced in the 1980s as a variable for detecting prostate cancer , the detection rate of prostate cancer has been increasing .
it is true that an abnormal finding on a dre or trus is an indication for prostate biopsy , but in the majority of cases , the psa level is the most important factor in deciding whether we will proceed with prostate biopsy .
however , it is reported that 30 to 40% of patients who test positive for prostate cancer in prostate biopsy proceeded when only the psa was increased without any abnormality in the dre or trus .
the specificity and sensitivity of psa can result in high values in other positive diseases .
the psa may increase not only in bph but also in urinary tract infection and bacterial prostatitis .
the psa can increase in acute inflammation and silent infection [ 7 - 9,12 ] .
also , some researchers have reported that treatment with antibiotics and anti - inflammatory drugs for chronic prostatitis can decrease the psa and the necessity for prostate biopsy .
nadler et al .   reported that the size and infection of the prostate can be a chief cause of psa increase in the case of patients not diagnosed with prostate cancer .
but irani et al .   reported that even if there is an infiltration of inflammatory cells in the prostatic interstitium , it is not related to the psa increase in the blood if the glandular epithelial cell layer is not destroyed at the same time .
furthermore , it has been reported that the existence of inflammatory cells of the interstitium or glandular tissue in the prostate biopsy has no statistical affiliation with the concentration of psa in the blood .
carver et al .   argued that national institutes of health ( nih ) category iv asymptomatic prostatitis increases the psa concentration in the blood , but its clinical significance is not that greatbecause the mean differences with the normal group are 2.3 ng / ml and 1.4 ng / ml , respectively .
reported that there is an increase of the concentration of psa in the blood in 71% of patients with acute prostatitis , 15% of patients with chronic prostatitis , and 6% of patients with nonbacterial prostatitis , but there was no psa increase in patients who showed only symptoms of chronic prostatitis .
found a relation of the psa concentration in the blood with acute and chronic prostatitis accompanied by clinical symptoms identified histologically , but no relation in the case of deactivated prostatitis .
chang et al .   investigated 223 patients who tested negative in a prostate biopsy by classifying the infection level and reached the conclusion that the whole size of the prostate is an important factor that contributes to the increase in the psa concentration in the blood , but that there was no relation with the prostatitis level .
the relationship of prostatitis and the psa increase continues to stimulate dispute , and we suggest that the findings mentioned above are not sufficient to explain the reason for the psa increase in the case of nih category iv asymptomatic prostatitis .
nadler et al .   investigated 421 patients with nih category iii chronic prostatitis and reported recently that the mean psa concentration in the blood of the patients investigated was 1.97 ng / ml . compared with the level in the normal group of 1.72 ng / ml , this was a statistically significant increase , but it is still below the normal psa range .
also , f - psa , percent f - psa , and the [ -2 ] ppsa isoform show some increase with prostate cancer , but they are inappropriate to be used as biomarkers of prostate cancer diagnosis because of their low specificity and sensitivity .
treatment with antibiotics in the case of chronic prostatitis and increased psa results in a very significant psa decrease .
but any special bacteria is found in 90% of cases of prostatitis with or without symptoms .
this kind of investigation of the changes in psa after treatment with antibiotics or anti - inflammatory drugs for nonbacterial prostatitis is uncommon . according to the report of potts   among 122 patients with an average psa increase of 9.35 ng / ml , 51 ( 42% ) patients
were diagnosed with infection by urinalysis after a massage of the prostate or prostatic secretion ( eps ) .
the patients were then treated with antibiotics for 4 weeks , and after 6 to 8 weeks they had a psa examination .
after the treatment , 22 of the 51 patients had a normal psa concentration ( average , 2.9 ng / ml ) and they did not need a prostate biopsy .
but there was a continuous increase of psa in the remaining 29 patients , and among them , 9 patients were diagnosed with prostate cancer . in comparison with patients diagnosed with cancer in prostate biopsy after treatment with antibiotics ,
the psa decrease in patients with benign biopsy results was significantly greater ( -1.3% vs. -21.3% ) . in the investigation carried out with 95 patients diagnosed with nonbacterial prostatitis and who showed an increase of psa , bozeman et al
.   proceeded with prostate biopsy in patients in whom the psa value did not decrease after 4 weeks of treatment with antibiotics and anti - inflammatory drugs . among these ,
the psa of 36.4% of patients decreased from 8.48 ng / ml to 5.39 ng / ml after treatment ; in 44 patients ( 46.3% ) the psa decreased below 4 ng / ml , so they avoided prostate biopsy . in the remaining patients who underwent prostate biopsy , 13 patients ( 25.5% )
were diagnosed with prostate cancer , 37 patients ( 72.5% ) with chronic infection , and 1 patient ( 1.05% ) with bph . among the patients diagnosed with prostate cancer , just 4.8% of patients had shown a psa decrease from 8.32 ng / ml to 7.92 ng / ml , which was not statistically significant .
therefore , the authors argued that chronic prostatitis is the chief cause of psa increase and that treatment for prostatitis can decrease unnecessary prostate biopsy .
but hochreiter   argued that although the authors of two investigations considered that the patients were not diagnosed with prostate cancer because the psa was decreased to less than 4 ng / ml , it was difficult to conclude that the patients in fact had no cancer .
it is not a certainty that psa - normalized patients are cancer free after antibiotic therapy .
there are no general guidelines that can be applied to all men with increased psa before prostate biopsy . in cases
in which the psa level is increasing , if we first exclude prostatitis and carry out a serial diagnostic procedure , it may help to reduce unnecessary prostate biopsy .

 purposewe aimed to reduce unnecessary prostatic biopsy in patients with high prostate - specific antigen ( psa ) by consideration of prostatic inflammation.materials and methodsthe investigation was conducted prospectively in 413 patients with a psa level of 4 to 10 ng / ml from january 2004 to december 2009 .
 all patients underwent the expressed prostatic secretion ( eps ) or voided bladder urine 3 ( vb3 ) test to be classified into two groups : positive group and negative group .
 patients with a positive result on the eps or vb3 test were treated with antibiotics for 2 months , and in cases in which the psa level remained high , we performed prostate biopsy . in patients with a negative result on the vb3 test , we performed prostate biopsy directly.resultsof the 413 study patients , 215 ( 52% ) patients had positive findings on the eps or vb3 test .
 after 8 weeks of antibiotics therapy , 53 of the 215 men avoided prostate biopsy because their psa level was normalized .
 the other patients ( 162 of 215 ) still had elevated psa levels of more than 4 ng / ml , including 7 patients in whom the biopsy revealed cancer .
 patients with negative findings ( 198 of 413 ) underwent prostate biopsy .
 of the 198 patients , 41 were diagnosed with prostate cancer .
 the total prostate cancer detection rate was 11.6% in our subjects , where as it was 20.7% in the patients with negative findings on the eps or vb3 and 3.3% in the patients with positive findings , respectively.conclusionsin cases in which the psa level is increasing , if we first exclude prostatitis and carry out a serial diagnostic procedure , it may help to reduce unnecessary prostatic biopsy .