Coxiella burnetii serostatus in dromedary camels (Camelus dromedarius) is associated with the presence of C. burnetii DNA in attached ticks in Laikipia County, Kenya.

AIMS: Q fever is a globally distributed, neglected zoonotic disease of conservation and public health importance, caused by the bacterium Coxiella burnetii. Coxiella burnetii normally causes subclinical infections in livestock, but may also cause reproductive pathology and spontaneous abortions in artiodactyl species. One such artiodactyl, the dromedary camel (Camelus dromedarius), is an increasingly important livestock species in semi-arid landscapes. Ticks are naturally infected with C. burnetii worldwide and are frequently found on camels in Kenya. In this study, we assessed the relationship between dromedary camels' C. burnetii serostatus and whether the camels were carrying C. burnetii PCR-positive ticks in Kenya. We hypothesized that there would be a positive association between camel seropositivity and carrying C. burnetii PCR-positive ticks. METHODS AND RESULTS: Blood was collected from camels (N = 233) from three herds, and serum was analysed using commercial ELISA antibody test kits. Ticks were collected (N = 4354), divided into pools of the same species from the same camel (N = 397) and tested for C. burnetii and Coxiella-like endosymbionts. Descriptive statistics were used to summarize seroprevalence by camel demographic and clinical variables. Univariate logistic regression analyses were used to assess relationships between serostatus (outcome) and tick PCR status, camel demographic variables, and camel clinical variables (predictors). Camel C. burnetii seroprevalence was 52%. Across tick pools, the prevalence of C. burnetii was 15% and Coxiella-like endosymbionts was 27%. Camel seropositivity was significantly associated with the presence of a C. burnetii PCR-positive tick pool (OR: 2.58; 95% CI: 1.4-5.1; p = 0.0045), increasing age class, and increasing total solids. CONCLUSIONS: The role of ticks and camels in the epidemiology of Q fever warrants further research to better understand this zoonotic disease that has potential to cause illness and reproductive losses in humans, livestock, and wildlife.

An irreversible inhibitor of 17ß-hydroxysteroid dehydrogenase type 1 inhibits estradiol synthesis in human endometriosis lesions and induces regression of the non-human primate endometriosis.

Endometriosis is a gynecological disorder affecting about 10% of women and can lead to invalidating painful symptoms and infertility. Since there is no current definitive cure for this disease, new therapeutic options are necessary. 17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is involved in the production of estradiol (E2), the most potent estrogen in women, and of 5-androstene-3ß,17ß-diol (5-diol), a weaker estrogen than E2, but whose importance increases after menopause. 17ß-HSD1 is therefore a pharmacological target of choice for the treatment of estrogen-dependent diseases such as endometriosis. We developed a targeted-covalent (irreversible) and non-estrogenic inhibitor of 17ß-HSD1, a molecule named PBRM, and herein evaluated its efficiency for the treatment of endometriosis. In a cell-free assay containing estrone (E1), the natural substrate of 17ß-HSD1, PBRM was able to block the formation of E2 in a collection of 50 human endometriosis lesions from a different clinical feature type, location, and phase. When given orally by gavage at 15 mg/kg to baboons, the resulting plasmatic concentration of PBRM was found to be sufficiently high (up to 125 ng/mL) for an efficacy study in a non-human primate (baboon) endometriosis model. After 2 months of treatment, the number of lesions/adhesions decreased in 60% of animals (3/5) in the PBRM-treated group, compared to the placebo group which showed an increase in the number of lesion/adhesions in 60% (3/5) of animals. Indeed, the total number of lesions/adhesions decreased in treated group (-6.5 or -19% when excluding one animal) while it increased in the control group receiving a placebo (+11%). Analysis of specific endometriotic lesions revealed that PBRM decreased the number of red lesions (-67%; 8/12) and white lesions (-35%; 11/31), but not of blue-black lesions. Similarly, PBRM decreased the surface area of dense adhesions and filmy adhesions, as compared to placebo. Also, PBRM treatment did not significantly affect the number of menstrual days. Finally, this targeted covalent inhibitor showed no adverse effects and no apparent toxicity for the duration of the treatment. These data indicate that 17ß-HSD1 inhibitor PBRM is a promising candidate for therapy targeting endometriosis and supports the need of additional efforts toward clinical trials.

Successful experimental infant baboon model for childhood cryptosporidiosis studies.

BACKGROUND: Cryptosporidiosis causes high morbidity and mortality in children under 2 years of age globally. The lack of an appropriate animal model that mimics the pathogenesis of disease in humans has hampered the development and testing of potential therapeutic options. This study aimed to develop and validate an infant baboon infection model of cryptosporidiosis. METHODS: Eighteen immunocompetent weaned infant baboons aged 12 to 16 months were used. The animals were n = 3 controls and three experimental groups of n = 5 animals each inoculated with Cryptosporidium parvum oocysts as follows: group 1: 2 × 104, group 2: 2 × 105, group 3: 2 × 106 followed by daily fecal sampling for oocyst evaluation. Blood sampling for immunological assay was done on the day of infection and weekly thereafter until the end of the experiment, followed by necropsy and histopathology. Statistical analysis was performed using R, SPSS, and GraphPad Prism software. Analysis of variance (ANOVA) and Bonferroni post hoc tests were used for comparison of the means, with p < 0.05 considered as a significant difference. Correlation coefficient and probit analysis were also performed. RESULTS: In all experimental animals but not controls, the onset of oocyst shedding occurred between days 2 and 4, with the highest oocyst shedding occurring between days 6 and 28. Histological analysis revealed parasite establishment only in infected animals. Levels of cytokines (TNF-α, IFN-γ, and IL-10) increased significantly in experimental groups compared to controls. CONCLUSION: For developing a reproducible infant baboon model, 2 × 104 oocysts were an effective minimum quantifiable experimental infection dose.

Evaluating Engagement in a Digital and Dietetic Intervention Promoting Healthy Weight Gain in Pregnancy: Mixed Methods Study.

BACKGROUND: Early excess and inadequate gestational weight gain (GWG) have been associated with negative outcomes for mother and child. The use of digital media to deliver pregnancy lifestyle interventions is increasing, but there is little data on participant engagement. The Pregnancy Lifestyle Activity and Nutrition (PLAN) intervention pilot study was an electronic health and dietetic-delivered intervention program promoting healthy GWG in early pregnancy. OBJECTIVE: This study aims to explore the interactions of participants with the program and to assess its acceptability. METHODS: This study uses both quantitative and qualitative methods using data from parent randomized controlled trial (ACTRN12617000725369). Quantitative data from 22 participants in the intervention arm who completed the study provided measures of the interactions participants had with the digital components of the program and with dietetic consultations. A descriptive qualitative analysis employed semistructured interviews with 9 participants to elicit views on the acceptability of the intervention and its components. RESULTS: The electronic delivery of information and recording of weight from 8 to 20 weeks of gestation were universally accepted. Component (face-to-face dietitian, weight tracker, website information delivery, and SMS goal prompting) acceptability and engagement differed between individuals. A total of 4 key themes emerged from the qualitative analysis: supporting lifestyle change, component acceptability and value, delivery platforms, and engagement barriers. CONCLUSIONS: The PLAN intervention and its delivery via a blend of personal dietetic consultations and digital program delivery was found to be acceptable and valuable to pregnant women. Individuals responded differently to various components, emphasizing the importance of including women in the development of lifestyle interventions and allowing participants to choose and tailor programs. Larger randomized controlled trials using these insights in a broader section of the community are needed to inform the iterative development of practical, time-efficient, and cost-effective ways of supporting optimal GWG with the potential to optimize outcomes for pregnant women and their child.

Endemicity of Yaws and Seroprevalence of Treponema pallidum Antibodies in Nonhuman Primates, Kenya.

Human yaws has historically been endemic to Kenya, but current epidemiologic data are lacking. We report seroprevalence for Treponema pallidum antibodies in olive baboons (Papio anubis) and vervet monkeys (Chlorocebus pygerythrus) in Laikipia County, Kenya. Our results suggest endemicity of the yaws bacterium in monkeys, posing a possible zoonotic threat to humans.

Monolithic 3D printing of embeddable and highly stretchable strain sensors using conductive ionogels.

Medical training simulations that utilize 3D-printed, patient-specific tissue models improve practitioner and patient understanding of individualized procedures and capacitate pre-operative, patient-specific rehearsals. The impact of these novel constructs in medical training and pre-procedure rehearsals has been limited, however, by the lack of effectively embedded sensors that detect the location, direction, and amplitude of strains applied by the practitioner on the simulated structures. The monolithic fabrication of strain sensors embedded into lifelike tissue models with customizable orientation and placement could address this limitation. The demonstration of 3D printing of an ionogel as a stretchable, piezoresistive strain sensor embedded in an elastomer is presented as a proof-of-concept of this integrated fabrication for the first time. The significant hysteresis and drift inherent to solid-phase piezoresistive composites and the dimensional instability of low-hysteresis piezoresistive liquids inspired the adoption of a 3D-printable piezoresistive ionogel composed of reduced graphene oxide and an ionic liquid. The shear-thinning rheology of the ionogel obviates the need to fabricate additional structures that define or contain the geometry of the sensing channel. Sensors are printed on and subsequently encapsulated in polydimethylsiloxane (PDMS), a thermoset elastomer commonly used for analog tissue models, to demonstrate seamless fabrication. Strain sensors demonstrate geometry- and strain-dependent gauge factors of 0.54-2.41, a high dynamic strain range of 350% that surpasses the failure strain of most dermal and viscus tissue, low hysteresis (<3.5% degree of hysteresis up to 300% strain) and baseline drift, a single-value response, and excellent fatigue stability (5000 stretching cycles). In addition, we fabricate sensors with stencil-printed silver/PDMS electrodes in place of wires to highlight the potential of seamless integration with printed electrodes. The compositional tunability of ionic liquid/graphene-based composites and the shear-thinning rheology of this class of conductive gels endows an expansive combination of customized sensor geometry and performance that can be tailored to patient-specific, high-fidelity, monolithically fabricated tissue models.

Expression Changes of Structural Protein Genes May Be Related to Adaptive Skin Characteristics Specific to Humans.

Human skin is morphologically and physiologically different from the skin of other primates. However, the genetic causes underlying human-specific skin characteristics remain unclear. Here, we quantitatively demonstrate that the epidermis and dermis of human skin are significantly thicker than those of three Old World monkey species. In addition, we indicate that the topography of the epidermal basement membrane zone shows a rete ridge in humans but is flat in the Old World monkey species examined. Subsequently, we comprehensively compared gene expression levels between human and nonhuman great ape skin using next-generation cDNA sequencing (RNA-Seq). We identified four structural protein genes associated with the epidermal basement membrane zone or elastic fibers in the dermis (COL18A1, LAMB2, CD151, and BGN) that were expressed significantly greater in humans than in nonhuman great apes, suggesting that these differences may be related to the rete ridge and rich elastic fibers present in human skin. The rete ridge may enhance the strength of adhesion between the epidermis and dermis in skin. This ridge, along with a thick epidermis and rich elastic fibers might contribute to the physical strength of human skin with a low amount of hair. To estimate transcriptional regulatory regions for COL18A1, LAMB2, CD151, and BGN, we examined conserved noncoding regions with histone modifications that can activate transcription in skin cells. Human-specific substitutions in these regions, especially those located in binding sites of transcription factors which function in skin, may alter the gene expression patterns and give rise to the human-specific adaptive skin characteristics.

Impact of the Levonorgestrel-Releasing Intrauterine System on the Progression of Chlamydia trachomatis Infection to Pelvic Inflammatory Disease in a Baboon Model.

Background: Understanding the relationship between the levonorgestrel (LNG)-releasing intrauterine system (IUS) and sexually transmitted infections (STIs) is increasingly important as use of the LNG-IUS grows to include women at higher risk for STIs. This study assessed the impact of the LNG-IUS on development of Chlamydia trachomatis pelvic inflammatory disease, using a baboon model. Methods: Baboons with and those without the LNG-IUS were cervically inoculated with C. trachomatis and monitored daily, and cervical and fallopian tube swab specimens were collected weekly for C. trachomatis quantitation by nucleic acid amplification testing and culture. Vaginal swab specimens were collected for cytokine analysis, and serum samples were obtained for detection of C. trachomatis antibodies. Results: The LNG-IUS resulted in an increased C. trachomatis burden in the cervix, with the bacterial burden in the LNG-IUS group diverging from that in the non-LNG-IUS group by 6 weeks after infection. One of 7 baboons in the non-LNG-IUS group and 2 of 6 in the LNG-IUS group developed pelvic inflammatory disease, while 3 animals in each group met criteria suggestive of pelvic inflammatory disease. LNG-IUS increased baseline interleukin 8 levels but failed to further upregulate interleukin 8 during infection. In LNG-IUS recipients, early perturbations in the interleukin 1ß axis corresponded to decreased C. trachomatis clearance and increased T-helper type 2 immune responses. Conclusion: LNG-IUS use results in delayed clearance of C. trachomatis and might alter the reproductive tract immune environment.

Prevalence and geographical distribution of Papio hamadryas papillomavirus 1 (PhPV1) in Kenyan baboons.

Papio hamadryas papillomavirus (PhPV) 1, 2, and 3, are Alphapapillomaviruses that have been detected in Kenyan Olive baboons but the distribution is unknown. Therefore, cervical screening for PhPV1 was performed in baboons from various areas in Kenya using a nested polymerase chain reaction. The prevalence rate was 33%.

c-Jun NH2-terminal kinase inhibitor bentamapimod reduces induced endometriosis in baboons: an assessor-blind placebo-controlled randomized study.

OBJECTIVE: To test the hypothesis that the c-Jun NH2-terminal kinase (JNK) inhibitor (JNKI) bentamapimod (AS602801/PGL5001) can reduce induced endometriosis in baboons. DESIGN: Prospective randomized placebo-controlled study. SETTING: Nonhuman primate research center. ANIMAL(S): Twenty baboons each underwent four laparoscopies. Initial screening laparoscopy (L1) was followed after one rest cycle by an endometriosis-induction laparoscopy (L2). Fifty days after L2, the baboons were randomized just before staging laparoscopy (L3). Treatment lasted for 60 days, followed by a post-treatment staging laparoscopy (L4). INTERVENTION(S): Randomization before a 60-day treatment in four groups: daily placebo (n = 5), daily oral administration of 20 mg/kg JNKI (n = 5), concomitant daily oral administration of 20 mg/kg JNKI and 10 mg medroxyprogesterone acetate (MPA; n = 5), or subcutaneous administration of 3 mg cetrorelix every 3 days (n = 5). MAIN OUTCOME MEASURE(S): Type, surface area and volume of endometriotic lesions, and revised American Society for Reproductive Medicine score and stage were recorded during L3 and L4. Menstrual cycle length and serum hormonal concentration were recorded before and after treatment. RESULT(S): Compared with placebo, treatment with JNKI, JNKI + PMA, or cetrorelix resulted in lower total surface area and volume of endometriotic lesions. Remodeling of red active lesions into white lesions was observed more frequently in baboons treated with JNKI + MPA than in baboons treated with JNKI only. Menstrual cycle length and serum hormonal concentration were similar between placebo and JNKI groups. CONCLUSION(S): JNKI alone was as effective as JNKI + MPA or cetrorelix in reducing induced endometriosis in baboons, but without severe side effects or effect on cycle length or serum reproductive hormones.

The levonorgestrel-releasing intrauterine system is associated with delayed endocervical clearance of Chlamydia trachomatis without alterations in vaginal microbiota.

Progestin-based contraception may impact women's susceptibility to sexually transmitted infection. We evaluated the effect of the levonorgestrel intrauterine system (LNG-IUS) on cervical persistence of Chlamydia trachomatis (CT) in a baboon model. Female olive baboons (Papio anubis) with or without an LNG-IUS received CT or sham inoculations. CT was detected in cervical epithelium with weekly nucleic acid amplification testing (NAAT) and culture. Presence of the LNG-IUS was associated with prolonged persistence of CT. Median time to post-inoculation clearance of CT as detected by NAAT was 10 weeks (range 7-12) for animals with an LNG-IUS and 3 weeks (range 0-12) for non-LNG-IUS animals (P = 0.06). Similarly, median time to post-inoculation clearance of CT by culture was 9 weeks (range 3-12) for LNG-IUS animals and 1.5 weeks (range 0-10) for non-LNG-IUS animals (P = 0.04). We characterized the community structure of the vaginal microbiota with the presence of the LNG-IUS to determine if alterations in CT colonization dynamics were associated with changes in vaginal commensal bacteria. Vaginal swabs were collected weekly for microbiome analysis. Endocervical CT infection was not correlated with alterations in the vaginal microbiota. Together, these results suggest that LNG-IUS may facilitate CT endocervical persistence through a mechanism distinct from vaginal microbial alterations.

The influence of quarantine on reproductive cycling in wild-caught Baboons (Papio anubis).

Stress impacts nonhuman primate menstrual cycle length but the impact of quarantine is unknown. A retrospective analysis was performed on cycle data from 31 wild-caught baboons during and following quarantine. Cycling initiated in 94 days (19-181) and length normalized within 4-6 cycles. Quarantine significantly impacts menstrual cycle length.

Menstrual endometrial supernatant may induce stromal endometriosis in baboons.

We tested the hypothesis that endometriosis can be induced in baboons more successfully by intra-pelvic injection of the pellet of menstrual endometrium when compared to its supernatant. Menstrual endometrium, separated into pellet (n = 5) and supernatant fractions ( n = 8), or phosphate buffered saline (1 ml, n = 7, controls) was injected laparoscopically into the pelvis. During laparoscopy 25 days later, the number (ρ = 0.027) and surface area (ρ <0.0001) of endometriosis-like lesions were significantly higher in the pellet group, than in the supernatant group, or in the control group. Histological typical endometriosis was present only in the endometrial pellet group (1/15), whereas stromal endometriosis was observed in both the pellet group (6/15), and the supernatant group (6/20). Peritoneal endometrial like glands were observed in both the endometrial pellet group (3/15), and in the supernatant group (1/20). In conclusion, we confirmed our hypothesis that endometriosis can be induced in baboons more successfully by intrapelvic injection of the pellet of menstrual endometrium when compared to its supernatant.

Ovarian tissue cryopreservation by vitrification in olive baboons (papio anubis): a pilot study.

BACKGROUND: Ovarian tissue cryopreservation by vitrification is an attractive technique for fertility preservation in women. However, this technique has not been optimized. The aim of this study was to evaluate the baboon as a model for the preclinical study of ovarian tissue cryopreservation by vitrification and thawing. METHODS: Ovarian cortical tissues (1-mm cubes) were obtained surgically from adult female olive baboons (n = 9) maintained in captivity and vitrified using dimethyl sulphoxide and ethylene glycol protocol. The proportion of morphologically intact follicles (primordial, primary and secondary) in paired fresh and cryopreserved (vitrified-thawed) ovarian tissues was compared. RESULTS: Overall, 67.1% of follicles were morphologically normal after vitrification. When compared to fresh ovarian tissue, vitrified-thawed ovarian tissue contained a comparable number of intact primordial follicles (48.9 vs. 52.9%), and a lower number of both primary (14.8 vs. 29.5%; p < 0.05) and secondary (2.0 vs. 0.7%; p < 0.05) follicles. CONCLUSION: After vitrification and thawing, baboon ovarian tissue retains about 67% of morphologically normal follicles, which is comparable to results for human ovarian tissue, and suggests that the olive baboon is a promising animal model for preclinical assessment of ovarian vitrification, thawing and autotransplantation studies.

Short-term effects of high-dose khat on sperm parameters and reproductive hormonal levels in olive baboons (Papio anubis).

The biological effects of khat (Catha edulis) on reproduction and fertility are inadequately investigated and controversial, hence we determined the effects of oral administration of high-dose khat on sperm parameters and male hormonal levels in olive baboons. In this study, 6 male baboons received a high dose of khat (500 g/week) during 1 month. Electroejaculation for sperm studies (concentration, motility and chromatin integrity) and plasma collection for hormonal analysis (testosterone, prolactin and cortisol) were done weekly during 1 month before and 1 month during khat administration as well as 2 weeks after the last dose of khat administration. Administration of khat extract induced a significant reduction in sperm motility (p = 0.008), sperm count (p = 0.041), sperm chromatin integrity (p = 0.0003), testosterone levels (p = 0.035) and prolactin levels (p = 0.0115), but not in cortisol levels and sperm volume (p > 0.05). The results suggest that high-dose khat decreases sperm quality and testosterone and hence may contribute to male infertility.

Aromatase inhibitor treatment limits progression of peritoneal endometriosis in baboons.

OBJECTIVE: To determine the effect of inhibiting aromatase activity on endometrial lesion growth and aromatase expression in a baboon model of induced endometriosis. DESIGN: Prospective study. SETTING: Primate research institute. ANIMAL(S): Sixteen olive baboons. INTERVENTION(S): Sixteen olive baboons with induced endometriosis were examined with laparoscopy 10 months after disease inoculation. Animals in group 1 (n = 10) were treated with 1.25 mg/d of the aromatase inhibitor (AI) letrozole, and animals in group 2 (n = 6) were given a placebo for a total of 6 months. MAIN OUTCOME MEASURE(S): Total number of endometriotic lesions, morphology, and volume of lesions, as well as semiquantitative reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction for levels of aromatase cytochrome messenger RNA were measured. Ovarian volumes were evaluated before treatment initiation and every 2 months during the study. RESULT(S): Treatment of group 1 animals with an AI significantly decreased lesion volume from baseline measurements, whereas the placebo-treated animals showed an increase in lesion volume. Aromatase messenger RNA levels in lesions in the AI-treated animals were significantly lower compared with the placebo-treated animals. Ovarian volumes were significantly increased at 6 months of AI treatment compared with pretreatment volumes. CONCLUSION(S): These findings suggest that suppression of aromatase cytochrome P450 may inhibit the in vivo growth of endometriotic lesions in baboons.

Baboon spermatology: basic assessment and reproducibility in olive baboons (Papio anubis).

BACKGROUND: Development of a reproducible baboon in vitro fertilization (IVF) system require optimized and reproducible sperm parameters. The objective of this study was to document basic spermatology values and investigate the reproducibility of these variables in the same baboons 1 or 3 months later in a larger number of baboons. METHODS: In this prospective study, sperm quality (semen volume, pH, concentration, motility, morphology and size) was evaluated in 27 sperm samples obtained from 9 baboons electroejaculated three times with a time interval of 1 month (between first and second sample collection) and 3 months (between second and third round sample collection). RESULTS: Baseline sperm values for semen volume (0.5 ± 0.3 ml), pH (7.5 ± 0.3), concentration (54.2 ± 19.3 million/ml), motility (67.3 ± 18.5%) and morphology (89.2 ± 4.8%) were similar to sperm samples obtained after 1 or 3 months (P > 0.05). Head, midpiece and tail abnormalities were rarely observed (0-9%). Sperm dimensions were characterized by a tail length of 69.6 ± 13.9 µm, a head width of 2.41 ± 0.43 µm and a head length of 3.49 ± 0.6 µm. CONCLUSION: Sperm quality was not affected by repeated electroejaculation with time intervals of 1 or 3 months, suggesting that the same baboon can participate multiple times in reproductive research.

The effects of a single cervical inoculation of Chlamydia trachomatis on the female reproductive tract of the baboon (Papio anubis).

BACKGROUND: The baboon (Papio hamadryas anubis) can be transcervically instrumented, facilitating studies of intrauterine contraception and reproductive tract infection. We sought to determine if the baboon could become infected with a single cervical inoculation of Chlamydia trachomatis. METHODS: Ten female baboons were randomized and inoculated cervically with C. trachomatis serovar E (or buffer alone). Animals underwent weekly clinical and laparoscopic evaluations for four weeks and at post-inoculation week 8, to monitor upper tract infection. Cervical culture and nucleic acid amplification testing (NAAT) were completed weekly throughout the study. Animals were euthanized at week 16 and the reproductive tracts were examined histologically. RESULTS: All inoculated animals developed cervical infection. The average duration of positive NAAT results was 6.8 weeks (range 2-16). Two of eight (25%) animals tested positive from fallopian tube samples. Infected animals showed histological findings consistent with chlamydial infection, such as germinal centers. Five of ten animals seroconverted to C. trachomatis. CONCLUSIONS: Baboons cervically inoculated once with C. trachomatis develop infection similar to humans, with a low incidence of upper tract infection. This novel model of Chlamydia infection closely resembles human disease and opens new avenues for studying the pathogenesis of sexually transmitted infections and contraceptive safety.

Randomized comparison of different ovarian stimulation regimens for assisted reproductive technology in baboons (Papio anubis).

OBJECTIVE: To compare different methods of ovarian stimulation (OS) for assisted reproductive technology in baboons. DESIGN: Prospective randomized study. SETTING: Institute of primate research. ANIMAL(S): Baboons (n = 10) were randomized into two groups (of five animals each) during three different cycles to compare six protocols of OS. INTERVENTION(S): Cycle 1: clomiphene citrate (CC) alone (group CC) versus CC and GnRH agonist (group CC-Ag); cycle 2: recombinant gonadotropins (GON) without GnRH agonist (group GON) versus GON and depot GnRH agonist (group GON-AgDepo-1); cycle 3: GON and depot GnRH agonist (group GON-AgDepo-2) versus GON and daily GnRH agonist in a classic long protocol (group GON-Ag). Oocyte aspiration was performed 34-36 hours after injecting 5,000 IU rhCG, followed by fertilization via intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S): Number and quality of oocytes retrieved and their fertilization rate. RESULT(S): More metaphase II (MII) oocytes were retrieved using the GON-AgDepo-1 (n = 12; 64% MII), GON-AgDepo-2 (n = 9; 79% MII), GON-Ag (n = 16; 88% MII), and GON (n = 6; 59% MII) protocols compared with the CC (n = 9; 15% MII) and CC-Ag (n = 14; 20% MII) protocols. Fertilization by ICSI varied between 43% and 71%. CONCLUSION(S): In baboons, long and depot protocols yield similar numbers of MII oocytes; however, depot protocol may be preferable because only one injection of GnRH agonist is needed.

Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study.

OBJECTIVE: To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. DESIGN: A preclinical and a clinical case-control trial. SETTING: Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. POPULATION: Pregnant and nonpregnant women and baboons receiving chemotherapy. METHODS: Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard-dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry. MAIN OUTCOME MEASURES: Area under the curve (AUC), maximal plasma concentration, terminal elimination half-life, clearance and distribution volume of each drug in pregnant and nonpregnant state. RESULTS: Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy. CONCLUSIONS: Although numbers were too small for statistical significance, pregnancy-associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long-term follow-up of women treated with chemotherapy during pregnancy is underscored.