PurposeTo evaluate transcytosis of immunoglobulin G (IgG) by the neonatal Fc receptor (FcRn) in adult primate intestine to determine whether this is a means for oral delivery of monoclonal antibodies (mAbs).MethodsRelative regional expression of FcRn and localization in human intestinal mucosa by RT-PCR, ELISA & immunohistochemistry. Transcytosis of full-length mAbs (sandwich ELISA-based detection) across human intestinal segments mounted in Ussing-type chambers, human intestinal (caco-2) cell monolayers grown in transwells, and serum levels after regional intestinal delivery in isoflurane-anesthetized cynomolgus monkeys.ResultsIn human intestine, there was an increasing proximal-distal gradient of mucosal FcRn mRNA and protein expression. In cynomolgus, serum mAb levels were greater after ileum-proximal colon infusion than after administration to stomach or proximal small intestine (1–5 mg/kg). Serum levels of wild-type mAb dosed into ileum/proximal colon (2 mg/kg) were 124 ± 104 ng/ml (n = 3) compared to 48 ± 48 ng/ml (n = 2) after a non-FcRn binding variant. In vitro, mAb transcytosis in polarized caco-2 cell monolayers and was not enhanced by increased apical cell surface IgG binding to FcRn. An unexpected finding in primate small intestine, was intense FcRn expression in enteroendocrine cells (chromagranin A, GLP-1 and GLP-2 containing).ConclusionsIn adult primates, FcRn is expressed more highly in distal intestinal epithelial cells. However, mAb delivery to that region results in low serum levels, in part because apical surface FcRn binding does not influence mAb transcytosis. High FcRn expression in enteroendocrine cells could provide a novel means to target mAbs for metabolic diseases after systemic administration.

To evaluate the incidence of disseminated Mycobacterium avium complex infection (DMAC) and to define the association between signs and symptoms and development of DMAC in patients with human immunodeficiency virus (HIV) infection, all cases of DMAC at Grady Memorial Hospital Infectious Disease Clinic (Atlanta) between 1985 and 1990 were reviewed, and a prospective study of the association of symptoms with DMAC was done. Between 1985 and 1990, DMAC occurred in 16% of patients with AIDS. Incidence increased from 5.7% in 1985-1988 to 23.3% in 1989-1990 (P less than .001). Median time from AIDS diagnosis to diagnosis of DMAC increased from 4.5 months in 1985-1988 to 8 months in 1989-1990 (P less than .02). In the prospective study, DMAC was seen only in persons with a CD4+ count less than 100 cells/mm3 and was associated with fever (P less than .03), anemia (P less than .001), weight loss (P less than .01), diarrhea (P less than .01), and elevated alkaline phosphatase (P less than .01). It is recommended that all such HIV-infected persons have mycobacterial blood cultures done.

Medial olivocochlear (MOC) efferent fibers synapse directly on the outer hair cells (OHCs). Efferent activation evoked by contralateral acoustic stimulation (CAS) will affect OHC amplification and subsequent measures of distortion-product otoacoustic emissions (DPOAEs). The aim of this study was to investigate measures of total and separated DPOAEs during efferent activation. Efferent activation produces both suppression and enhancement of the total DPOAE level. Level enhancements occurred near fine-structure minima and were associated with consistent MOC evoked upward shifts in DPOAE fine-structure frequency. Examination of the phase of the separated components revealed that frequency shifts stemmed from increasing phase leads of the reflection component during CAS, while the generator component phase was nearly invariant. Separation of the two DPOAE components responsible for the fine-structure revealed more consistent reduction of the levels of both components. Using vector subtraction (which takes into account both level and phase) to estimate the changes in the unseparated DPOAE provided consistent evidence of DPOAE suppression. Including phase information provided a more sensitive, valid and consistent estimate of CAS function even if one does not know the position of the DPOAE in the fine-structure.

Three postoperative analgesic protocols were assigned randomly to 24 healthy dogs after thoracotomy at the left fourth intercostal space. Morphine was administered parenterally to eight dogs after tracheal extubation; selective intercostal nerve blocks with bupivacaine hydrochloride and epinephrine were administered to eight dogs before closure of the thorax; and bupivacaine hydrochloride and epinephrine were administered through an interpleural catheter to eight dogs after tracheal extubation. Heart rate, respiratory rate, rectal temperature, hematocrit, plasma protein, blood gas, and pain score evaluations were recorded before surgery and 30 minutes, 1 hour, 2 hours, and 3 hours after extubation. Morphine caused significant decreases in blood pH and blood oxygen tensions, and significant increases in carbon dioxide tensions. Dogs treated with intercostal nerve blocks had no significant changes in these parameters, and dogs treated with interpleural bupivacaine had significant decreases in blood oxygen tension. All dogs had significant decreases in rectal temperature, and hypothermia was prolonged after morphine. Analgesia was initially adequate in most dogs, but some dogs in each treatment group had recurrence of pain and were treated with interpleural bupivacaine. One dog developed pneumothorax. Interpleural administration of bupivacaine produced analgesia equal to that produced by systemic administration of morphine or selective intercostal nerve block with bupivacaine. Bupivacaine was easily readministered through an interpleural catheter. Respiratory compromise was less in dogs treated with bupivacaine than in dogs treated with morphine. After intercostal thoracotomy, interpleural bupivacaine provided prolonged analgesia with fewer blood gas alterations than morphine.

Of 3,816 homosexual men examined in five sexually transmitted disease clinics in the United States, 6.1% had hepatitis B surface antigen, 52.4% had antibody to hepatitis B surface antigen, and 3.0% of the men who had no other indicator of infection with hepatitis B virus (HBV) had antibody to hepatitis B core antigen. The rate of seropositivity for HBV indicated by the presence of one or more of these serologic markers was 61.5%; seropositivity was significantly related to the duration of regular homosexual activity and to the number of nonsteady male sexual contacts in the four months before the patients were interviewed. Anal-genital intercourse, oral-anal intercourse, and rectal douching were significantly related to evidence of HBV infection, but oral-oral contact and oral-genital contact were not. Trauma to the rectal mucosa is a feature common to the practices that were significantly related to seropositivity for HBV.