Nonhuman primates: their role in assessing developmental effects of immunomodulatory agents

There are close physiologic similarities between humans and macaques that make them well suited for preclinical testing of biopharmaceutics. These include menstrual cycles of similar length and hormonal control, comparable cellular and endocrine processes of implantation, and similar timetables of prenatal development. Three teratogenic agents have induced abnormal development of the macaque thymus that is a key organ in the development of the fetal immune system. Embryonic exposure to triamcinolone acetonide, a potent corticosteroid, during critical periods of thymus development caused marked hypoplasia, depletion of thymic lymphocytes, and reduction of epithelial elements. Aplasia and hypoplasia of the thymus were a distinct feature of the "retinoid syndrome" in cynomolgus macaques following exposure to 13-cis-retinoic acid (Accutane) in early pregnancy, the time of neural crest migration. Experimentally induced zinc deficiency in rhesus macaques from conception to 1-year of age caused severe alterations in immunocompetence. More recent studies have shown that the levels of IgG and IgA in cervicovaginal lavages of the rhesus macaque exhibit specific temporal patterns during the normal menstrual cycle. Taken together, theses data suggest that several macaque species are appropriate animal models for preclinical safety assessment of immunomodulatory drugs. Current teratology protocols in these models may require slight modifications to adequately assess the safety of these biologics.     

Functional and Morphological Development of Lymphoid Tissues and Immune Regulatory and Effector Function in Rhesus Monkeys: Cytokine-Secreting Cells, Immunoglobulin-Secreting Cells, and CD5+ B-1 Cells Appear Early in Fetal Development

Little is known regarding the timing of immune ontogeny and effector function in fetal humans and nonhuman primates. We studied the organization of lymphocyte and antigen-presenting cell populations in developing lymphoid tissues of rhesus monkey fetuses during the second and third trimesters (65 to 145 days of gestation; term = 165 days). Immunoglobulin-secreting and cytokine-secreting cells were detected at day 80. The thymus, spleen, lymph nodes, and intestinal mucosa were examined for cells expressing CD3, CD5, CD20, CD68, p55, and HLA-DR. In the spleens of 65-day-old fetuses (early second trimester), the overwhelming majority of total lymphocytes were CD5⁺ CD20⁺ B-1 cells. The remaining lymphocytes were CD3⁺ T cells. By day 80, splenic B and T cells were equal in number. Intraepithelial CD3⁺ CD5⁻ T cells and lamina propria CD20⁺ CD5⁺ B cells were present in the intestines of 65-day-old fetuses. By day 80, numerous CD20⁺ CD5⁺ B cells were present in the jejunums and colons and early lymphocyte aggregate formation was evident. The spleens of 80- to 145-day-old fetuses contained immunoglobulin M (IgM)-secreting cells, while IgA-, IgG-, interleukin-6-, and gamma interferon-secreting cells were numerous in the spleens and colons. Thus, by the second trimester, the lymphoid tissues of the rhesus monkey fetus have a complete repertoire of properly organized antigen-presenting cells, T cells, and B cells.     

Community outreach programs and major adherence lapses with antiretroviral therapy in rural Kakamega,Kenya

We investigated features of major adherence lapses in antiretroviral therapy (ART) at public Emusanda Health Centre in rural Kakamega County, Kenya using medical records from 2008 to 2015 for all 306 eligible patients receiving ART. Data were modelled using survival analysis. Patients were more likely to lapse if they received stavudine (hazard ratio (HR) 2.54, 95% confidence interval (95%CI):1.44–4.47) or zidovudine (HR 1.64, 95%CI:1.02–2.63) relative to tenofovir. Each day a patient slept hungry per month increased risk of major adherence lapse by 3% (95%CI:0–7%). Isolated home visits by community health workers (CHWs) were more effective to assist patients to return to the health centre than isolated phone calls (HR 2.52, 95%CI:1.02–6.20).     

Acceptability of a Pilot Intervention of Voluntary Medical Male Circumcision and HIV Education for Street-Connected Youth in Western Kenya

Purpose

Street-connected youth (SCY) in Kenya and elsewhere in sub–Saharan Africa are at high risk of HIV. Voluntary Male Medical Circumcision (VMMC) reduces the risk of female-to-male HIV transmission. Circumcision is also a traditional coming-of-age process in many Kenyan ethnic groups. This paper describes the acceptability of VMMC delivered as part of a ten-day healing, educational, and ‘coming-of-age’ retreat implemented as a pilot with SCY.

Functional and morphological development of lymphoid tissues and immune regulatory and effector function in rhesus monkeys: cytokine-secreting cells,immunoglobulin-secreting cells,and CD5(+) B-1 cells appear early in fetal development

Little is known regarding the timing of immune ontogeny and effector function in fetal humans and nonhuman primates. We studied the organization of lymphocyte and antigen-presenting cell populations in developing lymphoid tissues of rhesus monkey fetuses during the second and third trimesters (65 to 145 days of gestation; term = 165 days). Immunoglobulin-secreting and cytokine-secreting cells were detected at day 80. The thymus, spleen, lymph nodes, and intestinal mucosa were examined for cells expressing CD3, CD5, CD20, CD68, p55, and HLA-DR. In the spleens of 65-day-old fetuses (early second trimester), the overwhelming majority of total lymphocytes were CD5(+) CD20(+) B-1 cells. The remaining lymphocytes were CD3(+) T cells. By day 80, splenic B and T cells were equal in number. Intraepithelial CD3(+) CD5(-) T cells and lamina propria CD20(+) CD5(+) B cells were present in the intestines of 65-day-old fetuses. By day 80, numerous CD20(+) CD5(+) B cells were present in the jejunums and colons and early lymphocyte aggregate formation was evident. The spleens of 80- to 145-day-old fetuses contained immunoglobulin M (IgM)-secreting cells, while IgA-, IgG-, interleukin-6-, and gamma interferon-secreting cells were numerous in the spleens and colons. Thus, by the second trimester, the lymphoid tissues of the rhesus monkey fetus have a complete repertoire of properly organized antigen-presenting cells, T cells, and B cells.     

Acceptability of Male Circumcision Among Adolescent Boys and their Parents,Botswana

Little is known of the acceptability of male circumcision (MC) to adolescent boys, a key target group for HIV prevention. We conducted a cluster design survey among adolescent boys and their parents/guardians in two villages in Botswana. Of 1300 households visited, 398 boys were eligible; 269 boys and 210 parents/guardians participated. MC was described correctly by 80% of boys, and 76% identified that MC reduces the risk of male HIV acquisition. After a brief informational session, 75% of boys stated that they would definitely want to be circumcised and 96% of parents/guardians would want their boy circumcised. Boys most frequently reported pain (49%) and possible health problems (19%) as concerns undergoing MC; concerns about peer or partner acceptance, sexual function, or cultural appropriateness were uncommon. Adolescent MC is likely to be highly acceptable in Botswana if done safely, for free and with adequate pain control in a hospital setting.     

Provision of low-aflatoxin local complementary porridge flour reduced urinary aflatoxin biomarker in children aged 6–18 months in rural Tanzania

Aflatoxins are toxic secondary metabolites of fungi that colonize staple food crops, such as maize and groundnut, frequently used in complementary feeding. In preparation for a large trial, this pilot study examined if provision of a low-aflatoxin infant porridge flour made from local maize and groundnuts reduced the prevalence of a urinary aflatoxin biomarker in infants. Thirty-six infants aged 6–18 months were included from four villages in Kongwa District, Tanzania. The study was conducted over 12 days with a three-day baseline period and a 10 days where low-AF porridge flour was provided. Porridge intake of infants was assessed using quantitative 24-h recalls by mothers. Household food ingredients used in infant porridge preparation and urine samples were collected on Days 1–3 (baseline) and 10–12 (follow-up). Aflatoxins were measured in household foods, and AFM1 was measured in urine. At baseline and follow-up, 78% and 97%, respectively, of the infants consumed porridge in the previous 24 h, with a median volume of 220 mL (interquartile range [IQR]: 201, 318) and 460 mL (IQR: 430, 563), respectively (p < 0.001). All 47 samples of homemade flour/ingredients were contaminated with AFs (0.3–723 ng/g). The overall prevalence of individuals with detectable urinary AFM1 was reduced by 81%, from 15/36 (42%) at baseline to 3/36 (8%) at follow-up (p = 0.003). Provision of low-aflatoxin porridge flour was acceptable to caregivers and their infants and successfully reduced the prevalence of detectable urinary AFM1 in infants, thus, confirming its potential to be tested in future large-scale health outcomes trial.     

A Cyber-Security Risk Assessment Methodology for Medical Imaging Devices: the Radiologists’ Perspective

Journal of Digital Imaging - Medical imaging devices (MIDs) are exposed to cyber-security threats. Currently, a comprehensive, efficient methodology dedicated to MID cyber-security risk assessment...     

13-cis-Retinoic acid alters neural crest cells expressing Krox-20 and Pax-2 in macaque embryos.

This study investigates hindbrain and associated neural crest (NCC), otocyst, and pharyngeal arch development in monkey embryos following teratogenic exposure to 13-cis-retinoic acid (cRA). cRA was orally administered (5 mg/kg) to pregnant long-tailed macaques (Macaca fascicularis) between gestational days (GD) 12 and 27. Embryos were surgically collected at desired stages during treatment, analyzed for external morphological changes, and processed for immunohistochemistry. Two transiently expressed nuclear proteins, Krox-20 and Pax-2, were used as markers for the target cellular and anatomical structures. Rhombomere (r) expression patterns of Pax-2 (r4/r6) and Krox-20 (r3/r5) were maintained after cRA treatment, but r4 and r5 were substantially reduced in size. In untreated embryos, Krox-20 immunoreactive NCC derived from r5 migrated caudally around the developing otocyst to contribute to the third pharyngeal arch mesenchyme. In cRA-treated embryos, a subpopulation of NCC rostral to the otocyst also showed Krox-20 immunoreactivity, but there was a substantial reduction in Krox-20 post-otic NCC. Pax-2 immunoreactive NCC migrating from r4 to the second pharyngeal arch were substantially reduced in numbers in treated embryos. Alteration in the otic anlage included delayed invagination, abnormal relationship with the adjacent hindbrain epithelium, and altered expression boundaries for Pax-2. cRA-associated changes in the pharyngeal arch region due to cRA included truncation of the distal portion of the first arch and reduction in the size of the second arch. These alterations in hindbrain, neural crest, otic anlage, and pharyngeal arch morphogenesis could contribute to some of the craniofacial malformations in the macaque fetus associated with exposure to cRA.