Introduction {#S6}
============

Human immunodeficiency virus (HIV)-1-infected patients are at risk of developing HIV-1 associated neurocognitive disorders (HAND) \[[@R1], [@R2]\]. These disorders progress over time, ranking from mild neurocognitive impairment to HIV-1-associated dementia, which involves severe cognitive dysfunction in multiple domains \[[@R3]\]. The introduction of antiretroviral therapy (ART) has reduced the prevalence of dementia. However, as the lifespan of HIV-1 infected patients has been prolonged by ART, the prevalence of HAND with aging remains high \[[@R4]\].

HAND probably arises from direct and maintained viral invasion of the central nervous system (CNS), which is an important reservoir for HIV-1 virus regardless of plasma viral suppression or cumulative time on ART. In the North-East AIDS Dementia consortium, over 50% of viremically controlled HAND patients had detectable virus in the cerebrospinal fluid (CSF) \[[@R5]\]. Aberrant macrophage and T-lymphocyte activation in the CSF continued despite viremic control by ART \[[@R6]\], and brain atrophy correlated with the CSF level of quinolinic acid, evidence of activated CNS macrophages and microglia associated with neuroinflammation and excitotoxicity \[[@R7]\].

HIV-1 infection of the brain stimulates both the innate and adaptive immune systems.. Brain damage and neuronal loss are associated with activation of microglia, astrocytes and invasive macrophages, which release toxic quantities of agents such as nitric oxide, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and interleukin (Il)-1β \[[@R8]\]. Additionally, preclinical evidence indicates that there is secondary activation of phospholipases A~2~ (PLA~2~) that release of the n−6 polyunsaturated fatty acid arachidonic acid (AA) from membrane phospholipids \[[@R9]\]. AA and many of its eicosanoid products are proinflammatory. They include prostaglandin (PG)E~2~ formed preferentially by cyclooxygenase (COX)-2, thromboxane (TX)B~2~ formed preferentially by COX-1, 15 (S)-HETE formed by 15-lipoxygenase (LOX), lipoxin (LX)A~4~ formed from 15-HETE by 5-LOX \[[@R10]\], leukotriene (LT)B~4~ also derived from AA by 5-LOX \[[@R11]\], 15-epi-LXA~4~ synthesized from 15 (R)-HETE by acetylated COX-2 \[[@R12], [@R13]\], and isoprostanes produced by non-enzymatic pathways \[[@R14], [@R15]\]. COX-2 expression is increased following injection of HIV-1 Tat or gp-120 proteins into rodent brain, and in other HIV-1 rodent models \[[@R16]--[@R20]\].

Evidence for neuroinflammation in HIV-1 patients, and the recognized relation between neuroinflammation and upregulated AA metabolism in animal HIV-1 models and human neurodegenerative disease \[[@R21]--[@R23]\], suggest that antiinflammatory drugs that target the brain AA cascade might be of clinical relevance. One such drug is aspirin (ASA, acetylsalicylic acid), whose antiinflammatory actions in peripheral inflammation are well described \[[@R24], [@R25]\]. ASA inhibits COX-1, which converts AA to TXB~2~, while acetylating and inhibiting COX-2, which converts AA to PGE~2~ and also becomes capable of converting docosahexaenoic acid (DHA) to antiinflammatory 17R-hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins \[[@R26]\]. Evidence in animals and humans indicates that even low dose aspirin can exert behavioral and other biological effects in the intact CNS \[[@R27]--[@R32]\].

To provide a basis for testing potential efficacy of ASA in HIV-1 patients with HAND, we examined in the present study the effect of low-dose ASA on brain AA and DHA metabolism in a transgenic (Tg) rodent model of HIV-1, and in control rats. The human HIV-1 provirus, carrying seven out of the nine HIV-1 genes after functional deletion of the infectious genes *Gag* and *Pol* is constitutively expressed by the HIV-1 Tg rat. The HIV-1 Tg rat develops neuropathology as it ages, thus may be an animal model for HAND \[[@R33], [@R34]\]. It shows reduced spatial learning at 5 months of age. At 7--9 months, neuroinflammation and synaptic loss occur, associated with increased expression of AA-metabolizing cytosolic cPLA~2~ IVA, secretory sPLA~2~ IIA and COX-2 \[[@R19]\] and changes in fatty acid composition \[[@R35]\].

We treated 9-month old HIV-1 Tg and wildtype rats with 10 mg/kg/day ASA in drinking water for 42 days, using ASA-free water as a control. This ASA regimen is equivalent to a low therapeutic dose of 100 mg in human (for a 70 kg subject) \[[@R36]--[@R38]\]. We used ELISA assays to measure brain concentrations of PGE~2~, thromboxane TXB~2~, leukotriene LTB~4~, lipoxin LXA~4~, 15-epi-LXA~4~, 15-hydroxyeicosatetraenoic acid (HETE), 8-isoprostane and resolvin D1.

Materials and Methods {#S7}
=====================

Chemicals {#S8}
---------

ASA was purchased from Sigma-Aldrich (Saint Louis, MO). Hexane and isopropanol (Reagent Grade) were obtained from Fisher Scientific (Pittsburgh, PA). Ultra-pure water was purchased from KD Medical (Columbia, MD).

Animals {#S9}
-------

The experiments were conducted under an approved NICHD animal protocol (12--027) in accordance with the NIH Guidelines on the Care and Use of Laboratory Animals. Age-matched male HIV-1 Tg or Fischer 344/NHsd wildtype rats (9 months-old), purchased from Harlan Laboratories (Madison, WI) were housed in an animal facility under a 12 h/12 h light--dark cycle with *ad libitum* access to water and an identical Teklad global 18% protein 2018S diet. The diet was 2018S (sterilized) for controls and 2918 (irradiated 2018S) for HIV-1 Tg rats (Teklad Harlan, Madison, WI). The diets were processed in identical ways, except that the 2018S diet was further gamma irradiated to minimize the risk of infection in the HIV-1 Tg colony. The diet contained (as % of total fatty acid) 16.7% saturated, 21.8% monounsaturated, 54.8% linoleic acid, 6.2% α-linolenic acid, 0.03% AA, 0.02% eicosapentaenoic (EPA, 20:5 n−3) and 0.06% docosahexaenoic acid (DHA, 22:6 n−3) \[[@R35]\]. After 42 days on the diet, the rats were anesthetized with Nembutal (40 mg/kg, i.p.), and subjected to head-focused microwave irradiation at 5.5 kW for 3.4 sec (Cober Electronics, Stamford, CT). The brain was immediately removed, placed on dry ice, and stored at −80 °C.

ASA treatment {#S10}
-------------

Before going on the diet, rats were separated into four different groups (n = 12): untreated wildtype, untreated HIV-1 Tg, ASA-treated wildtype, and ASA-treated HIV-1 Tg. Untreated groups received regular drinking water. The ASA-treated groups received ASA in water (10 mg/kg/day) for 42 days. Fresh ASA drinking water was prepared and provided every two days, as was control drinking water. Rat weight and water intake were monitored weekly. According to an interspecies conversion factor based on body surface, the 10 mg/kg/day dose used here was equivalent to a dose of 100 mg for a 70 kg person \[[@R36]\].

Sample preparation {#S11}
------------------

Extraction of oxygenated metabolites of AA and DHA was performed according to the Radin method \[[@R39]\]. Half-brains were homogenized in a glass Tenbroeck homogenizer in hexane-isopropanol (3:2 v:v, 18 ml/g brain). The homogenate was transferred to a glass centrifuge tube and the homogenizer was washed twice with 4 volumes of hexane-isopropanol solution. The pooled homogenate was centrifuged at 1500 rpm for 5 min at room temperature, and the organic supernatant was collected. The pellet was re-extracted twice in 5 ml hexane-isopropanol. The pooled extracts were dried under N~2~ at 45 °C, resuspended in 3 ml hexane-isopropanol and stored at −80 °C.

Measurement of brain eicosanoids and docosanoids by enzyme immunoassay {#S12}
----------------------------------------------------------------------

To perform an enzyme immunoassay, 1 ml of the sample in hexane-isopropanol was dried under N~2~ and resuspended in 500 µl buffer. Concentrations of eicosanoids or docosanoids were determined with commercially available ELISA kits in accordance with the manufacturer's instructions. PGE~2~ and 15-epi-LXA~4~ kits were obtained from Oxford Biochemical (Oxford, MI) and TXB~2~, LTB~4~, 15-HETE, LXA~4~, 8-isoprostane and Resolvin D1 kits were from Cayman Chemicals (Ann Arbor, MI).

Statistical analyses {#S13}
--------------------

All data are expressed as mean ± SEM (n = 10--12 per group). In some groups, an outlier was identified using Grubbs' test, and removed from the data set (as indicated in the figure legend). For 8-isoprostane quantification, n = 10 for controls and n = 11 for HIV-1 Tg rats due to sample shortage. A two-way ANOVA was performed to identify global effects of genotype and treatment (GraphPad Prism 5.0, GraphPad Software, La Jolla, CA), and was followed by Least Significant Difference (LSD) post-hoc tests for multiple comparison. The level of significance was set at p \< 0.05.

Results {#S14}
=======

Body weight {#S15}
-----------

There was a significant main effect of genotype on body weight. HIV-1 Tg rats weighed significantly less than wildtype controls (−20%, p \< 0.001). No effect of ASA treatment was observed.

Brain Metabolites {#S16}
-----------------

The brain concentrations of AA-derived metabolites and Resolvin D1 in HIV-1 Tg and wildtype rats are shown [Figure 1](#F1){ref-type="fig"}.

PGE~2~ -- A two-way ANOVA showed a significant effect of ASA on brain PGE~2~ levels (p = 0.009), but no effect of genotype. Post-hoc analysis by an LSD test indicated that the brain PGE~2~ concentration was significantly lowered by ASA treatment in HIV-1 Tg rats, compared to nontreated HIV-1 Tg rats (−66%, p = 0.006).

TXB~2~ -- There was no effect of genotype or ASA treatment on brain TXB~2~ concentration.

15-HETE -- There was no significant effect of genotype or ASA treatment on brain 15-HETE concentration.

12-HETE -- 12 HETE levels in most samples were below the limit of detection (196 pg/mL).

Statistical comparisons therefore were not performed.

LXA~4~ -- There was no effect of genotype or ASA treatment on brain LXA~4~ concentration.

LTB~4~ -- Brain LTB~4~ concentration did not significantly differ between untreated HIV-1 Tg and wildtype rats. However, a post-hoc test showed that LTB~4~ concentration was significantly lower in HIV-1 Tg rats that received ASA, compared to untreated animals (−29%, p = 0.03).

15-epi-LXA~4~ -- A two-way ANOVA showed a significant effect of ASA on brain 15-epi-LXA~4~ levels (p = 0.02), but no effect of genotype. Post-hoc analysis by LSD test showed that 15-epi-LXA~4~ concentration was significantly (2.1. fold) higher in HIV-1 Tg compared to wildtype rats (p = 0.04). This increase was prevented by ASA treatment in HIV-1 Tg rats, compared to non-treated (−62%, p = 0.01).

8-Isoprostane -- Two-way ANOVA showed a significant effect of HIV-1 Tg genotype (p = 0.01) on 8-isoprostane concentration, as well as a significant effect of ASA treatment (p = 0.04). There also was a significant HIV-1 genotype × ASA interaction (p = 0.02). Subsequent post-hoc tests indicated that the levels of 8-isoprostane in untreated HIV-1 Tg rats were significantly increased (p = 0.02) compared to levels in the wildtype rats. ASA treatment resulted in a lower 8-isoprostane level in HIV-1 Tg compared to wildtype, which approached statistical significance (p = 0.06).

Resolvin D1 -- We found no significant effect of genotype or ASA treatment on brain resolvin D1 concentration.

Discussion {#S17}
==========

Whole brain 15-epi-LXA~4~ and 8-isoprostane concentrations were higher in 9 month-old HIV-Tg rats than in wildtype controls that had been administered drinking water for an additional 42 days. In contrast, treatment with low-equivalent dose ASA for 42 days significantly reduced the increases in 15-epi-LXA~4~ and 8-isoprostane concentrations seen in the HIV-1 Tg compared to wildtype rats. Chronic ASA compared with aspirin also reduced brain PGE~2~ and LTB~4~ concentrations in HIV-1 Tg rats, but not in wildtype controls. In comparison, ASA treatment did not change the level of any other measured AA-derived eicosanoid in wildtype rats.

ASA directly inhibits COX-1 and limits COX-2 activity *via* acetylation, and therefore reduces the production of AA-derived prostaglandins \[[@R13], [@R24]--[@R26]\]. COX-1 and COX-2 catalyze the production of PGH~2~ from AA, which subsequently is converted to PGE~2~ by PG synthase or to TXB2 by TX synthase \[[@R40]\]. Our results showed a significant global effect of ASA on brain PGE~2~ concentration, particularly in HIV-1 Tg rats, in which ASA treatment reduced PGE~2~ concentration by 66%. This difference may correspond to upregulation of COX-2 in the brain HIV-1 Tg rats, whereas COX-1 is unchanged \[[@R19]\]. It suggests that ASA is more effective in a system where inflammatory processes are already activated. The ability of low-dose ASA to reduce the overproduction of brain PGE~2~ confirms that low dose ASA has a central effect when administered peripherally, and agrees with prior preclinical and clinical evidence of a central action \[[@R27]--[@R32]\]. ASA crosses the blood-brain barrier and can directly target central PG synthesis, although the effective dose reaching the brain might increase if barrier integrity is altered by pathology \[[@R41], [@R42]\].

TXB~2~ is measured as a marker for unstable TXA~2~, which has potent vasoconstrictor function and facilitates platelet aggregation. ASA treatment inhibits TXA~2~ synthesis in blood at doses as low as 40 mg/day in humans \[[@R43], [@R44]\], and is recommended in the prevention of cardiovascular complications. In this study, however, the brain TXB~2~ level was not reduced by ASA.

AA can be converted to 15 (S)-HETE by 15-LOX, which is elevated in brain from 9-month HIV-1 Tg compared to wildtype rats \[[@R19]\]. Although its role in brain remains to be explored, 15-HETE has been detected in different brain regions \[[@R45]\] and shown to trigger constriction in piglet cerebral arterioles \[[@R46]\]. In this study, however, the concentration of 15 (S)-HETE was unchanged by the HIV-1 genotype or by ASA treatment. The synthesis of the stereoisomer 15 (R)-HETE is triggered by ASA *via* acetylation of COX-2 \[[@R25]\]. 15 (R)-HETE was not measured in this study because an ELISA assay method is not available to specifically determine its level.

Lower levels of 15-HETE were detected compared to levels of PGE~2~. This might be explained by the use of commercial kits and possible difference in extraction efficiency depending on the metabolites. Additionally, negative interference may have affected detection of 15-HETE in the assay. Negative interference is associated with the composition of the sample and can arise from cross-reactants, heterophilic antibodies, or endogenous interferers \[[@R47]\]. Since our extraction process for lipid mediators removed proteins, the negative interference could have been caused by reduced binding of 15-HETE or lowered binding affinity of 15-HETE to its specific antibodies by interfering substances.

5-LOX is involved in the synthesis of LXA~4~ from 15-HETE, or *via* the production of LTA~4~ from 5-HETE \[[@R10]\]. LXA~4~ is a mediator in the resolution of inflammation in various animal models, including stroke \[[@R48], [@R49]\], and also was increased in cultured HIV-1 infected monocytes and astroglia \[[@R50]\]. The brain LXA~4~ level was not impacted by the HIV-1 genotype or by ASA treatment in the present study.

The brain 15-epi-LXA~4~ concentration was significantly higher in untreated HIV-1 Tg rats than in wildtype controls, but this effect was absent following ASA treatment. 15-epi-LXA~4~ is an ASA-triggered anti-inflammatory AA-derived mediator that is synthesized from 15 (R)-HETE by acetylated COX-2 \[[@R12], [@R13]\]. Increased 15-epi-LXA~4~ concentration may reflect the brain response to increased pro-inflammatory eicosanoid production in HIV-1 Tg rats.

Brain LTB~4~ was lowered by ASA in HIV-1 Tg rats. Derived from AA conversion by 5-LOX. LTB~4~ is involved in pro-inflammatory signaling by promoting vascular permeability and leukocyte adhesion and activation \[[@R11]\]. LTB~4~ also has been implicated in chronic inflammatory diseases such as asthma \[[@R51]\], rheumatoid arthritis \[[@R52]\] and irritable bowel disease \[[@R52]\].

The concentration of the PGF~2~-like compound 8-isoprostane was significantly higher in HIV-1 Tg compared to wildtype brain, but the elevated 8-isoprostane level was reduced to a control level by ASA, suggesting that low-dose ASA reduced oxidative stress in the pathological brain. 8-Isoprostane is produced by non-enzymatic peroxidation of AA by free radicals and has been used as a marker of oxidative stress \[[@R53], [@R54]\]. Accumulation of free radicals and redox imbalance were observed in brain tissue from HIV-1 infected patients who died with dementia \[[@R55], [@R56]\]. The 8-isoprostane level also was increased by the HIV-1 tat protein in microglial cell culture \[[@R57]\]. F2-isoprostanes have been reported in CSF of patients with Alzheimer and other neuroinflammatory diseases \[[@R54], [@R58]\], and might be examined in CSF of HIV-1 patients.

Changes in brain AA-derived eicosanoid concentrations occurred despite the reported lack of change in brain esterified and unesterified AA concentrations in the HIV-1 Tg rat model \[[@R35]\]. These results are not inconsistent, since eicosanoid levels are 3 to 4 orders of magnitude lower than their AA substrate concentration, about 12000 nmol/g (25000 times the concentration of the most abundant eicosanoid detected, 8-isoprostane. Furthermore, a 3.6 fold increase in 8-isoprostane concentration in the HIV-1 Tg group would result in a \< 0.5% change in brain AA concentration, which would not be detected using the gas-chromatography method \[[@R35]\].

Resolvin D1 is DHA-derived metabolite that is a precursor to 10(R), 17(S) hydroxyl-DHA, which has potent anti-inflammatory properties in brain \[[@R59], [@R60]\]. Neither ASA nor genotype affected the concentration of resolvin D1. According to the manufacturer, the kit that we used is selective for 17 (S)-resolvin D1 isomer. However, ASA can trigger the synthesis of protective 17-(R)-resolvin D1 in response to inflammatory stress \[[@R26]\] and thus it would be important in the future to quantify this isomer using LC-MS-MS.

A limitation of this study is that we used Fisher 344/NHsd controls from which the HIV-1 line was derived, instead of littermate controls. We did this to be consistent with our previous study on HIV-1 Tg rats \[[@R35]\]. We cannot rule out possible confounding effects of genetic drift in the Fisher 344/NHsd line, but we consider this unlikely. At an extreme, the limitation may affect our interpretation of whether HIV-1 Tg rats have higher eicosanoid concentrations than control littermates specifically, but it would not alter our conclusions with regard to ASA, which significantly reduced several eicosanoid concentrations in the HIV-1 Tg rats.

In summary, chronic low dose human equivalent ASA blocked the increases in AA-derived LTB~4~ and 8-isoprostane concentrations that were produced in 9-month old HIV-1 Tg compared with wildtype rats, which show demonstrable pathology, behavioral changes and upregulated expression of AA metabolizing enzymes, including cPLA~2~, sPLA~2~ and COX-2. ASA also reduced 15 (S)-HETE and PGE~2~ concentrations in HIV-1 Tg rats. Thus, treatment with low dose ASA may dampen brain inflammation associated with upregulated brain AA metabolism and potentially contributing to the presence and progression of HAND. ASA in HIV-1 patients is well tolerated, and chronic low dose ASA is recommended for reducing cardiovascular events in HIV-1 patients \[[@R61], [@R62]\], although only one in five HIV-1 patients are actually taking ASA \[[@R61], [@R62]\]. In this regard, other nonsteroidal inhibitors of COX-2 have been shown to be beneficial on peripheral markers of disease severity in HIV-1 patients \[[@R63]--[@R65]\].

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

The authors declare no conflict of interest.

The authors thank Lisa Chang and Mei Chen for skillful technical assistance. The research was supported by the Intramural Research Program of the National Institute on Aging.

AA

:   arachidonic acid

ART

:   antiretroviral therapy

ASA

:   acetylsalicylic acid

CNS

:   central nervous system

COX

:   cyclooxygenase

CSF

:   cerebrospinal fluid

DHA

:   docosahexaenoic acid

HAND

:   HIV-1 associated neurocognitive disorders

HETE

:   hydroxyeicosatetraenoic acid

HIV

:   human immunodeficiency virus

LOX

:   lipoxygenase

LT

:   leukotriene

LX

:   lipoxin

PG

:   prostaglandin

PLA

:   phospholipase

TX

:   thromboxane

![Effects of HIV-1 genotype and low dose aspirin (ASA) on concentrations of PGE~2~, TXB~2~, 15-HETE, LXA~4~, LTB~4~, 15-epi-LXA~4~, 8-isoprostane, and Resolvin D1 in microwaved rat brain. Data are means ± SEM (n=10--12) and were analyzed using a two-way ANOVA followed by LSD post-hoc test. \* p \< 0.05, \*\* p \< 0.01. Some outliers were identified using the Grubbs' test, therefore n = 11 for PGE~2~: wildtype ASA and HIV-1 ASA, LXA~4~: wildtype water and HIV-1 ASA, LTB~4~: HIV-1 ASA, epi-LXA~4~: wildtype water, wildtype ASA and HIV-1 ASA, Resolvin D1: HIV-1 ASA. Variability of the 15-HETE assay was high, with outliers removed from the four groups.](nihms661138f1){#F1}

1.  Even treated HIV-1 patients can develop neurocognitive disorders.

2.  We studied a transgenic rat model of HIV-1, free of infectious Gag or Pol genes.

3.  The model had high brain 15-epi-lipoxin A4 and 8-isoprostane concentrations.

4.  These and other brain changes were prevented by chronic low-dose aspirin.

5.  Low-dose aspirin enters brain and might be used to treat HIV-1 neuroinflammation.


With multiple publications still gleefully dissecting the failures of a recent Rolling Stone exposé on campus rape, granting rape skeptics an unusually warm national spotlight, a new report from an unlikely corner of American culture confirms just how real the problems with reporting sex abuse in American higher education can be.

On Thursday, the Christian nonprofit ministry GRACE (an acronym for Godly Response to Abuse in the Christian Environment) released its long-awaited report on the mishandling of sex abuse allegations at Bob Jones University, the South Carolina school that for most of a century has served as the flagship institution of fundamentalist Christianity in the United States. The report is at once a grim autopsy detailing just how badly college administrators botched the handling of sexual abuse and rape claims, and also an example of surprising transparency from one of the most cloistered and conservative schools in the country.

In the 301-page report, GRACE shows Bob Jones University responding to rape and abuse claims with woeful ignorance of state law, a near-complete lack of training in psychology and trauma counseling best practices, and an overarching campus culture that blames women and girls for any abuse they suffer, and which paints all sexuality-from rape to consensual sex-as equivalent misdeeds.

That a fundamentalist institution-one most famous for banning interracial dating up until 14 years ago-has also been cartoonishly terrible at handling rape claims is not much of a surprise. But that Bob Jones University commissioned and, albeit with some serious reluctance, allowed the publication of this damning report is a major new contribution to the current debate on campus rape.

In November 2012, Bob Jones University (BJU) asked GRACE to serve as an independent ombudsman, reviewing how the school had handled claims of sex abuse, rape, and harassment over the years. Coming on the heels of the devastating revelations of sex abuse at Penn State, BJU leaders publicly said that the school was just being proactive.

Privately, they acknowledged a controversy closer to home had forced their collective hand

, when a BJU board member made national news for the way he'd handled a rape in his home church in New Hampshire, when, in 1997, a minor girl in his congregation became pregnant as a result of being raped by a church deacon, and the victim was made to confess her "sin" before the church before being shipped out of state for her confinement. The story was the last straw for a network of alienated BJU alumni, and the school was feeling increasing pressure to respond.

They turned to GRACE, a Christian anti-sex abuse organization founded by Boz Tchividjian, a Liberty University Law School professor, former prosecutor of child sex abuse cases, and also grandson of beloved evangelist Billy Graham.

Tchividjian and GRACE had been slowly gaining notice in the world of conservative Christianity for years, as the founder argued that the Protestant world was teetering on a sex abuse crisis as large as that of the Catholic Church. Under Tchividjian's leadership, GRACE had undertaken two previous investigations of large Christian missionary groups where numerous "missionary kids" alleged that serious child physical and sexual abuse had gone unpunished for years. (I covered the work of GRACE and its investigations in a lengthy profile for the May/June 2014 issue of The American Prospect.)

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GRACE's work wasn't always greeted with appreciation

, and in the midst of the Bob Jones investigation, GRACE was fired by one of the missionary groups that had commissioned an investigation, and prohibited from sharing its findings. In early January of this year, when GRACE was just months away from publishing its findings on BJU, that school also fired GRACE, suddenly and inexplicably, demanding a halt to the investigation. The story at that time covered a long list of dismaying allegations that Bob Jones had responded to reports of rape, child physical and sexual abuse, and sexual harassment with a mixture of incompetence, insensitivity and, in some cases, what looked like retaliation. After national coverage of the university's firing of GRACE, and intense student and alumni criticism, in February BJU rehired the organization to continue the investigation. But many alumni who'd grown up in the insular and tightly-controlled world of Bob Jones and its network of affiliated churches doubted that the school would ever allow the report to come out.

Now, two years after it began, the report, which draws on an immense amount of research, has seen the light of day. Its findings are based in part on survey responses from 924 people, interviews with 116, including 54 self-identified victims of sexual abuse, and 22 written statements. More than half (52.7 percent) of the abuse survivors said that the school's response to their disclosures had been "somewhat to very hurtful," and approximately 48 percent said that BJU either discouraged or directly told them not to make a police report. Among those who never disclosed their abuse to school officials, most explained that the atmosphere and teachings at BJU had convinced them not to talk to school officials about what had happened.

There were many reasons why BJU seemed to fail its student victims so thoroughly, but the problem seemed to start with the state of counseling at the school, which wasn't just limited to a student mental health center, but was an active part of daily life. Residence halls were overseen by "Dorm Counselors" who served as a first line of both help and discipline for students. Students who broke one of BJU's long list of possible infractions were assigned weekly counseling sessions as punishment. And BJU's ultimate disciplinary enforcer, longtime Dean of Students Jim Berg, was also active in both counseling individual students and heading up BJU's academic counseling program.

But what BJU called counseling wasn't exactly based on psychology's best practices; instead the school relied on a sort of psychology-alternative known as biblical counseling, common in fundamentalist circles, which argues the Bible is sufficient treatment for almost all mental and emotional problems-and that the root of most people's problems is sin. To become a biblical counselor didn't require degrees or experience in psychology or training, but only a strong grounding in the Bible. Indeed, Berg's only degrees were in Bible studies and theology, and his knowledge of counseling victims of sex abuse came from reading a few books and attending one conference-training he acknowledged to GRACE was "paltry among the research" that is available.

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Unsurprisingly, the pattern of treatment that victims at Bob Jones experienced was poorly suited to their needs. When Berg was told of students who alleged abuse or rape, he usually met with them for only one to three sessions, and bragged to a colleague that "in five minutes I can tell you what is wrong with somebody," and provide them with the proper sheet of scripture verses, "and say go study this and you will be all right."

Berg often began to immediately ask them probing, accusative questions about their own "moral life": whether they had been drinking or using drugs when assaulted, whether they were using them at present, whether they watched pornography or indulged in sexual fantasies-and, for women, whether they had experienced pleasure while being raped. One alleged victim says that when she told Berg about being raped by a coworker, he told her "there is a sin that happens behind every other sin," and they had to figure out what hers was. Though Berg told GRACE he didn't recall this, in a training video he made that GRACE reviewed, he explains that he asks alleged victims these uncomfortable questions at the beginning of their counseling because "I have to find out where there is guilt that they have to deal with."

While Berg suggested this was merely to separate victims' potential guilt about related issues-if, say, they had been raped after they lied to their parents about where they were going that night-and not to make them feel they were to blame, that's not necessarily the message those he counseled heard. As one rape victim who spoke to Berg explained to me last spring, "I already had a plate full of shame when I walked into Dr. Berg's office, and he put more shame on that, more than I could bear."

Another colleague of Berg's was even more explicit in suggesting that abuse victims shared culpability for what happened to them. Dr. Walter Fremont, a BJU professor and author of a book on Christian counseling used at the school, suggested as an example of a victim who needed to repent for her part in the sin "a teenage girl who only takes a bath when her mother is away from the home and leaves the bathroom door unlocked, inviting the father's corruptness."

After rapid-fire meetings with Berg or other high-level BJU staff, student victims were often handed off to their dorm counselors for ongoing advisement. But the dorm counselors were untrained fellow students with little or no understanding of the issues, nor even rudimentary knowledge of principles of counselors' confidentiality. One abuse victim's counselor told her boyfriend about the victim's disclosure, and the boyfriend went on share it with a member of the victim's family. Other counselors took it upon themselves to call a victim's family or home pastor. Another student with a complaint, upon realizing her dorm counselor knew nothing about sexual abuse, had to bring the counselor a book about the subject. One student who sought help for an eating disorder says her counselor admitted she knew nothing about the topic, and then went on to ask the counselee for dieting tips in preparation for her upcoming wedding.

Oftentimes, the counseling went beyond ineptitude to direct shaming, when counselors directed the victims to examine their own sins in relation to the abuse. Some said that counselors told them their PTSD symptoms, such as nightmares and flashbacks, were sinful, because they were choosing "to replay pornographic thoughts." And numerous victims said that they were told, while they may or may not be responsible for the abuse perpetrated against them, they were responsible for their response, and that it was sinful to be bitter and unforgiving. Some were told they should contact their abusers to ask their forgiveness for harboring anger and bitterness against them.

There were other systemic problems in BJU's counseling program. The same staff in charge of counseling were also often involved in BJU's disciplinary infrastructure-in a school where students could get in significant trouble for an astonishing array of infractions, from not keeping their rooms clean enough to going off campus without permission. Students routinely were expelled without notice.

In an uneasy mix of roles, Jim Berg served as both the head counselor and head disciplinarian. But the problem was broader than his particular purview, as victims described an environment where they were afraid to come forward to get help after being raped, because they feared being punished for breaking another rule during their attack. One student who was struggling with the revelation of her childhood abuse told GRACE she was placed on disciplinary counseling after she was caught smoking cigarettes, and Chancellor Bob Jones III attempted to impose an even harsher sentence of restricting her to campus for a semester.

Particularly harrowing was the experience of a student who alleged that her pastor had been raping her since she was 15, and who came to BJU officials when she became pregnant as a result of ongoing coercive sex with the pastor. But because she had lied about going off campus to meet him, BJU kicked her out of school.

BJU officials defended its comingling of counseling and discipline as something that made sense within the school's enduring adherence to the practice of in loco parentis- the quasi-parental role that most colleges abandoned fifty years ago-but students described its effect as both chilling and retaliatory.

Lastly, school officials also seemed almost completely ignorant of their legal obligations as mandatory reporters of sexual abuse. Berg explained to GRACE that he didn't learn about mandatory reporting requirements until 1992-decades after South Carolina enacted its mandatory reporting law-and even after learning that, he says he believed for years that the school was only obligated to make reports about sexual abuse that happened at the school involving BJU employee. The school also failed to understand that crimes other than forcible rape also fell under mandatory reporting laws, and, Berg told GRACE, school officials had treated issues like nonconsensual touching or molestation as moral, rather than criminal, offenses. (As recently as 2012, when there was a complaint of a sexual assault between two men on campus, BJU's new chief of public safety told GRACE that BJU officials appeared not to understand that this was a crime.)

GRACE's report concludes with a series of 26 recommended actions for BJU, ranging from a public apology to providing (off-campus) counseling services to hiring a victim's advocate. Significantly, they recommended the school cease sales of the books and training materials authored by school counseling staff, including Jim Berg and Walter Fremont, and to restrict Berg from any counseling role-or any public speaking about counseling-both at BJU and elsewhere. It also recommended unspecified personnel action against Chancellor Bob Jones III.

The apology has already been made. On Wednesday, the night before the report was released, the university called a school-wide meeting. There, BJU President Steve Pettit, (appointed just last summer), apologized for what the report would reveal. "We did not live up to [students'] expectations. We failed to uphold and honor our own core values. We are deeply saddened to hear that we added to their pain and suffering," he said. "To them I would say-we have carefully listened to your voice. We take your testimony in this report to our hearts. We intend to thoroughly review every aspect and concern outlined in the investigation and respond appropriately."

In a statement, GRACE's Tchividjian praised BJU's transparency and the precedent it might set for other Christian institutions. "Though much in this report will understandably cause readers to grieve, GRACE is encouraged by the willingness of Bob Jones University to take the unprecedented step to voluntarily request this independent investigation and to make these difficult findings public," he said.

But the precedent it could set, and the implicit challenge it represents, should go far beyond Christendom. However well BJU lives up to its promises in the months and years to come, the question people should be asking next is: If a school like BJU, with its bred-in-the-bone mistrust of the outside world, will ultimately allow this level of scrutiny, when will we see the same thing from schools that should know better?

Related: Read "By Grace Alone," Kathyrn Joyce's May/June report about the Bob Jones University rape and sex-abuse scandal.


Travelling with Parrots is relatively simple – but your & your family need to plan things well in advance.

Desensitization – this situation is simplified if you are going to drive with them in my experience. Typically, parrots travel very, very well-as long as you prepare them and, then yourself. Begin to desensitize them to their traveling “crate” as soon as you can.

Carrier choice – You need to place one or two perches across an appropriately sized plastic cat carrier. A simple “dowel” likely won’t do for proper grip so, finding Dragonwood or other perches through online bird stores that have more of a grip-texture that would be better for your birds. You’ll also need to place a towel in the bottom of the carrier and have extras with you on the road to change out daily. You can also purchase (online) appropriately sized stainless steel water and food bowls that will attach to the doorway of the kennel. I strongly recommend you do not use plastic bowls with birds like this-while you will think they may not destroy them-the moment you leave them unattended in the carrier and look elsewhere/take your eyes off of them- they usually will.

Celltie is an excellent company who makes carriers that are soft sided, easily secured, very easy to clean, mobile & light to carry. They already have perches in them with appropriate water bowls that come with them as well. However, they are little more expensive-if you do decide to purchase one of these for your bird – Ensure you get the stainless steel mesh and not the plastic mesh! While the latter is cheaper, for the same reasons noted above-stainless steel is better-the birds really have to try hard to get out of them. My Caique made easy work of chewing the plastic mesh once during a 20 minute commute to my practice with her – this was well after she was used to the carrier! Finally, Celltei carriers are also very convenient for travel-I move my birds exclusively in these carriers. Also- the company is very good about the occasional repair from one of my more robust parrots.

If you are traveling the winter or colder months – Celltie also makes fleece covers for the carriers that are absolutely perfect. If you don’t have towels over the carriers or have the ability to towel them-you will need to consider this depending on the length of time your on the road and in keeping with the birds 12 hour light cycle.

Tolerizing your bird to the carrier & travelling – Once you “desensitize” your bird by placing them in the carrier and rewarding them for perching, do some interactive enrichment as well and possibly even some foraging exercises which are “self-rewarding” activity for them to actually play in the carrier and get used to being in an enclosed space. And you increase the time in the carrier over days and weeks until your hundred percent comfortable that they are 100% comfortable in them or as best as they can be. Consider taking your bird on short day-trips for progressively longer times.

You’ll also need to bring bottled water with you and try not to change the brand while you’re traveling. You will also likely need to bring some form of suction cup perch also available online from various distributors so that you can have them perch at points in the hotel room or, more appropriately in the bathroom tub and if needed, you can shower them.

Ensure that you also bring their favorite food and treats but, you must be certain that every night they eat and drink well and try to keep them on their light cycle as much as possible. Of course you can leave some water and food in the carriers while you’re traveling.


import 'package:test/test.dart';
import 'package:sqlparser/sqlparser.dart';

import 'utils.dart';

void main() {
  test('parses insert statements', () {
    testStatement(
      'INSERT OR REPLACE INTO tbl (a, b, c) VALUES (d, e, f)',
      InsertStatement(
        mode: InsertMode.insertOrReplace,
        table: TableReference('tbl', null),
        targetColumns: [
          Reference(columnName: 'a'),
          Reference(columnName: 'b'),
          Reference(columnName: 'c'),
        ],
        source: ValuesSource([
          Tuple(expressions: [
            Reference(columnName: 'd'),
            Reference(columnName: 'e'),
            Reference(columnName: 'f'),
          ]),
        ]),
      ),
    );
  });

  test('insert statement with default values', () {
    testStatement(
      'INSERT INTO tbl DEFAULT VALUES',
      InsertStatement(
        mode: InsertMode.insert,
        table: TableReference('tbl', null),
        targetColumns: const [],
        source: DefaultValues(),
      ),
    );
  });

  test('insert statement with select as source', () {
    testStatement(
      'REPLACE INTO tbl SELECT * FROM tbl',
      InsertStatement(
        mode: InsertMode.replace,
        table: TableReference('tbl', null),
        targetColumns: const [],
        source: SelectInsertSource(
          SelectStatement(
            columns: [StarResultColumn(null)],
            from: TableReference('tbl', null),
          ),
        ),
      ),
    );
  });

  group('parses upsert clauses', () {
    const prefix = 'INSERT INTO tbl DEFAULT VALUES ON CONFLICT';
    test('without listing indexed columns', () {
      testStatement(
        '$prefix DO NOTHING',
        InsertStatement(
          table: TableReference('tbl'),
          targetColumns: const [],
          source: DefaultValues(),
          upsert: UpsertClause(action: DoNothing()),
        ),
      );
    });

    test('listing indexed columns without where clause', () {
      testStatement(
        '$prefix (foo, bar DESC) DO NOTHING',
        InsertStatement(
          table: TableReference('tbl'),
          targetColumns: const [],
          source: DefaultValues(),
          upsert: UpsertClause(
            onColumns: [
              IndexedColumn(Reference(columnName: 'foo')),
              IndexedColumn(
                Reference(columnName: 'bar'),
                OrderingMode.descending,
              ),
            ],
            action: DoNothing(),
          ),
        ),
      );
    });

    test('listing indexed columns and where clause', () {
      testStatement(
        '$prefix (foo, bar) WHERE 2 = foo DO NOTHING',
        InsertStatement(
          table: TableReference('tbl'),
          targetColumns: const [],
          source: DefaultValues(),
          upsert: UpsertClause(
            onColumns: [
              IndexedColumn(Reference(columnName: 'foo')),
              IndexedColumn(Reference(columnName: 'bar')),
            ],
            where: BinaryExpression(
              NumericLiteral(2, token(TokenType.numberLiteral)),
              token(TokenType.equal),
              Reference(columnName: 'foo'),
            ),
            action: DoNothing(),
          ),
        ),
      );
    });

    test('having an update action without where', () {
      testStatement(
        '$prefix DO UPDATE SET foo = 2',
        InsertStatement(
          table: TableReference('tbl'),
          targetColumns: const [],
          source: DefaultValues(),
          upsert: UpsertClause(
            action: DoUpdate(
              [
                SetComponent(
                  column: Reference(columnName: 'foo'),
                  expression: NumericLiteral(2, token(TokenType.numberLiteral)),
                ),
              ],
            ),
          ),
        ),
      );
    });

    test('having an update action with where', () {
      testStatement(
        '$prefix DO UPDATE SET foo = 2 WHERE ?',
        InsertStatement(
          table: TableReference('tbl'),
          targetColumns: const [],
          source: DefaultValues(),
          upsert: UpsertClause(
            action: DoUpdate(
              [
                SetComponent(
                  column: Reference(columnName: 'foo'),
                  expression: NumericLiteral(2, token(TokenType.numberLiteral)),
                ),
              ],
              where: NumberedVariable(
                QuestionMarkVariableToken(fakeSpan('?'), null),
              ),
            ),
          ),
        ),
      );
    });
  });
}