Dietary requirement for serum-derived bovine immunoglobulins in the clinical management of patients with enteropathy.

A variety of human disease conditions are associated with chronic intestinal disorders or enteropathies that are characterized by intestinal inflammation, increased gut permeability, and reduced capacity to absorb nutrients. Such disruptions in the homeostasis of the gastrointestinal (GI) tract can lead to symptoms of abdominal pain and discomfort, bloating, abnormal bowel function, and malabsorption of nutrients. While significant advances have been made in understanding the factors that influence the complex and fragile balance between the gut microbiota, intestinal epithelial cell integrity, and the underlying immune system, effective therapies for restoring intestinal balance during enteropathy are still not available. Numerous studies have demonstrated the ability of oral immunoglobulins to improve weight gain, support gut barrier function, and reduce the severity of enteropathy in animals. More recently, studies in humans provide evidence that serum-derived bovine immunoglobulin/protein isolate is safe and improves nutritional status and GI symptoms in patients with enteropathy associated with irritable bowel syndrome or infection with the human immunodeficiency virus. This review summarizes studies showing the impact of enteropathy on nutritional status and how specially formulated bovine immunoglobulins may help restore intestinal homeostasis and nutritional status in patients with specific enteropathies. Such protein preparations may provide distinct nutritional support required for the dietary management of patients who, because of therapeutic or chronic medical needs, have limited or impaired capacity to digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or other special medically determined nutrient requirements that cannot be satisfied by changes to the normal diet alone.

Oral serum-derived bovine immunoglobulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy.

OBJECTIVES: To examine the impact of serum-derived bovine immunoglobulin, an oral medical food known to neutralize bacterial antigen and reduce intestinal inflammation, on restoration of mucosal immunity and gastrointestinal function in individuals with HIV enteropathy. DESIGN: Open-label trial with intensive 8-week phase of bovine serum immunoglobulin (SBI) 2.5 g twice daily with a 4-week washout period and an optional 9-month extension study. METHODS: HIV enteropathy was defined as chronic gastrointestinal symptoms including frequent loose or watery stools despite no identifiable, reversible cause. Upper endoscopy for tissue immunofluorescent antibody assay and disaccharide gut permeability/absorption studies were performed before and after 8 weeks of SBI to test mucosal immunity and gastrointestinal function. Blood was collected for markers of microbial translocation, inflammation, and collagen kinetics. A validated gastrointestinal questionnaire assessed changes in symptoms. RESULTS: All eight participants experienced profound improvement in symptoms with reduced bowel movements/day (P = 0.008) and improvements in stool consistency (P = 0.008). Gut permeability was normal before and after the intervention, but D-xylose absorption increased in seven of eight participants. Mucosal CD4 lymphocyte densities increased by a median of 139.5 cells/mm2 from 213 to 322 cells/mm2 (P = 0.016). Intestinal-fatty acid binding protein (I-FABP), a marker of enterocyte damage, initially rose in seven of eight participants after 8 weeks (P = 0.039), and then fell below baseline in four of five who continued receiving SBI (P = 0.12). Baseline serum I-FABP levels were negatively correlated with subsequent rise in mucosal CD4 lymphocyte densities (r = -0.74, P = 0.046). CONCLUSION: SBI significantly increases intestinal mucosal CD4 lymphocyte counts, improves duodenal function, and showed evidence of promoting intestinal repair in the setting of HIV enteropathy.

Clot-inducing minerals versus plasma protein dressing for topical treatment of external bleeding in the presence of coagulopathy.

BACKGROUND: Previous studies identified WoundStat (WS, smectite) and Combat Gauze (CG, kaolin-coated gauze) as the most effective available agents for controlling arterial bleeding with potential utility in casualty care. Tissue sealant properties of WS suggested its potential advantage over clot-promoting CG for treating coagulopathic bleeding. This study compared the efficacy of CG and WS with a fibrinogen-based (FAST) dressing to control bleeding in coagulopathic animals. METHODS: Coagulopathy was induced in pigs (n = 55, 35 kg) by ∼50% isovolemic hemodilution and hypothermia (core temperature, 33°C ± 0.5°C). A 6-mm arteriotomy was made in the femoral artery and free bleeding allowed for 30 seconds. A test agent (n = 13-15 per group) or control product (gauze, GZ, n = 12) was applied to the wounds and compressed with a Kerlix gauze for 2 minutes. Fluid resuscitation was given, titrated to a mean arterial pressure of 65 mm Hg. Animals were observed for 180 minutes or until death. Angiography using the computed tomography method was performed on survivors, and local tissues were collected for histology. RESULTS: No differences were seen in baseline measures. Coagulopathy, confirmed by a 31% increase in prothrombin time and a 28% reduction in clotting strength (maximum amplitude, thrombelastography assay), was similar in all groups before injury. The average pretreatment blood loss was 11.9 mL/kg ± 0.4 mL/kg with no difference among groups. Posttreatment blood loss, however, was significantly different (p = 0.015) ranging from 18.2 mL/kg ± 8.8 mL/kg (FAST) to 63.3 mL/kg ± 10.2 mL/kg (GZ controls). Stable hemostasis was achieved in 10 of 13 (FAST), 5 of 15 (CG), 2 of 15 (WS), and 1 of 12 (GZ) animals in each group, resulting in significantly different survival rates (8-77%; p = 0.001). The average survival times were 145 (FAST), 119 (CG), 75 (WS), and 74 (GZ) minutes for different groups (p < 0.002). The outcomes with the FAST dressing were significantly better than with WS or GZ in this coagulopathic bleeding model. Essentially, no difference was found between WS and GZ control. Computed tomography images showed limited blood flow only through the vessels treated with FAST dressings. Histologic observations of the vessels indicated minimal damage with FAST and CG and greater injury with WS with some residues present on the tissues. CONCLUSION: The tissue sealant property of WS is apparently mediated by clot formation in the wound; therefore, it was ineffective under coagulopathic conditions. CG was partially effective in maintaining blood pressure up to 1 hour after application. FAST dressing showed the highest efficacy because of the exogenous delivery of concentrated fibrinogen and thrombin to the wound, which bypasses coagulopathy and secures hemostasis.

A community outbreak of hepatitis A in a religious community in Indiana: failure of immune serum globulin to prevent the spread of infection.

An outbreak of hepatitis A occurred in a religious community in Indiana, USA. Sixty-nine cases were ascertained among the 4466 residents over a year, and the highest attack rate was in children. The management of the outbreak included the widespread use of prophylactic immune serum globulin (ISG). Despite this, further cases occurred. To guide further ISG administration, a survey was undertaken to ascertain what proportion remained susceptible to HAV infection. From a random sample of 600 people in the affected community 440 saliva specimens (73%) were obtained. Of these, 12.5% were found to be immune (95% confidence intervals from 9-16%). No changes were made to the ISG administration policy. There was no evidence to suggest that administration of ISG had any effect on the duration of the outbreak. There was a low rate of symptomatic infection among young children (less than 10 years); as ISG does not prevent the spread of the virus its use is not recommended in future outbreak situations.

[The effect of the BITO preparation and various serum antioxidants on the intensity of lipid peroxidation in thermal trauma]. / Vliianie preparata BITO i nekotorykh syvorotochnykh antioksidantov na intensivnost' protsessov perekisnogo okisleniia lipidov pri termicheskoi travme.

Content of primary, secondary and final products of lipid peroxidation as well as the rate of the antioxidant activity were studied within various periods following thermic burns. At the same time, these patterns were estimated in vivo and in vitro after treatment with BITO preparation containing mainly alpha- and beta-globulins, ceruloplasmin and transferrin.

Role in nude mice of interferon and natural killer cells in inhibiting the tumorigenicity of human hepatocellular carcinoma cells infected with hepatitis B virus.

The human hepatoma cell line, PLC/PRF/5, which is persistently infected with hepatitis B virus (HBV), has integrated HBV-DNA, secretes HBV surface antigen (HBsAg), and does not grow readily in congenitally athymic (nu/nu) mice. The present investigation was undertaken to ascertain whether the low tumorigenicity of this cell line was governed by a host immune response and/or was related to expression of HBsAg. Subcutaneous injection of 4-5 X 10(6) cells into BALB/c nude mice produced localized encapsulated tumors with morphologic features of primary hepatocellular carcinoma in 25% of the animals within 29-40 d. No tumor growth was observed at lower cell inocula. In contrast, SK-HEP-1, an HBV-negative human hepatoma cell line, produced tumors at 1-5 X 10(6) cells inocula in 66% of the animals. Immunosuppression of mice with antilymphocyte serum (ALS) or irradiation increased tumor incidence in mice inoculated with 1 X 10(6) PLC/PRF/5 cells to almost 100% and produced local invasiveness. Immunosuppression also reduced the latency, i.e., time to tumor appearance, and increased mean tumor weight. These results suggest that tumorigenicity was limited by the host immune response. The nature of the response was delineated by treating nude mice challenged with tumor cells with sheep anti-mouse interferon globulin (anti-IFN). When 2 X 10(6) cells were injected, tumor growth occurred in 75% of anti-IFN-treated mice, whereas controls injected with the same number of cells, but not receiving anti-IFN, failed to develop tumors. The tumors in the anti-IFN-treated mice were highly invasive and the latency period until tumor appearance was reduced to 3-5 d. An inverse correlation was found between susceptibility of the hepatoma cells to natural killer (NK) activity in vitro and resistance to tumor growth in vivo. In vitro cytotoxicity for PLC/PRF/5 cells was eliminated by anti-NK 1.1 and complement, establishing the effector cell as an NK cell. NK cell activity 14 d after inoculation of mice with PLC/PRF/5 cells was augmented against PLC/PRF/5 target cells but not against SK-HEP-1 cells. Treatment of mice with ALS, irradiation, or anti-IFN abolished NK activity against PLC/PRF/5 cells. Co-cultivation of nude mouse spleen cells with PLC/PRF/5 but not with HBsAg or SK-HEP-1 cells induced secretion of murine IFNalpha. These results suggest that the IFN/NK cell system may play a role in limiting tumorigenicity and invasiveness of HBV-infected human hepatocellular carcinoma cells by a mechanism similar to that found for other cells persistently infected with viruses.

Transport of propranolol and lidocaine through the rat blood-brain barrier. Primary role of globulin-bound drug.

Basic lipophilic drugs such as propranolol and lidocaine are strongly bound by alpha(1)-acid glycoprotein, also called orosomucoid. Although the liver is known to rapidly clear plasma protein-bound propranolol or lidocaine, it is generally regarded that peripheral tissues, such as brain or heart, are only exposed to the small fraction of drug that is free or dialyzable in vitro. The "free drug" hypothesis is subjected to direct empiric testing in the present studies using human sera and an in vivo rat brain paradigm. Serum from 27 human subjects (normal individuals, newborns, or patients with either metastatic cancer or rheumatoid arthritis) were found to have up to a sevenfold variation in orosomucoid concentrations. The free propranolol or lidocaine as determined in vitro by equilibrium dialysis at 37 degrees C varied inversely with the orosomucoid concentration. Similarly the rate of transport of propranolol or lidocaine through the blood-brain barrier (BBB) was inversely related to the existing serum concentration of orosomucoid. However, the inhibition of rat brain extraction of drug by orosomucoid in vivo was only about one-fifth of that predicted by free drug measurements in vitro. This large discrepancy suggested orosomucoid-bound drug was readily available for transport into brain in vivo. Studies using purified human orosomucoid in the rat brain extraction assay also showed that orosomucoidbound propranolol or lidocaine is readily transported through the BBB. Conversely, albumin-bound propranolol or lidocaine was not transported through the BBB. The studies using albumin provide evidence that the in vivo rat brain paradigm used in the present investigations is capable of confirming, when possible, predictions made by the "free drug" hypothesis. These data suggest that the amount of circulating propranolol or lidocaine that is available for transport into a peripheral tissue such as brain is not restricted to the free (dialyzable) moiety but includes the much larger globulin-bound fraction. Therefore, existing pharmacokinetic models should be expanded to account for the transport of protein-bound drugs into peripheral tissues similar to what is known to occur in liver.

Continuous enrichment of albumin in relation to globulins in plasma.

This in vitro study deals with the problem of continuous separation of albumin from globulins in patient's plasma and reinfusion of the useful components of the plasma to the patient as the substitution fluid during a plasma exchange (PE) treatment. A cascade filtration system is developed to generate continuously two plasma fractions, one rich in globulins and the other rich in albumins, using two filters (H1P100 filter with a molecular weight cutoff 100,000 and Diafilter 20 with a molecular weight cutoff 30,000). For example, the system is able to increase the albumin/globulin ratio of plasma from 0.42 to 1.98, and the albumin concentration in the secondary plasma fraction is about seven times higher than that in the primary plasma fraction. This system is expected to be clinically useful in eliminating the side effects inherent in the usage of any other substitution fluid during a PE treatment.

Closing the Rh immune globulin utilization gap.

A simple and effective system, designed to achieve 100% utilization of Rh immune globulin in a general hospital, is presented. During a one-year period, all Rh-negative women exposed to events capable of inducing Rh sensitization were identified. In every case the protection of these women was verified. Four major oversights were discovered and immediately corrected, resulting in adequate protection of all Rh-negative women at risk of Rh sensitization. The system is compared with two other successful programs currently in use. The role of the Pathology Department, as a fail-safe mechanism to close potential loopholes in a Rh prophylaxis program, is emphasized.

Long-term blood pressure changes in renal homotransplantation.

Long-term blood pressure changes were studied in 50 patients who had undergone renal homotransplantation. Excluded were those subjects with arterial stenosis of the transplanted kidney, acute or rapidly progressive rejection, or recurrent glomerulonephritis, as well as those retaining their own diseased kidney(s). The blood pressure after the end of the first year was stable and, therefore, was utilized as the reference blood pressure for this study. One year after transplantation, hypertension was observed in 20% of the patients. Mean blood pressure was positively correlated with age (P less than .01), body weight (P less than .001), and serum creatinine level (P less than .001), and negatively correlated with maintenance dose of prednisone (P less than .01). A higher incidence of hypertension was observed in cadaver kidney transplantation than in living related-donor transplantation. The study minimizes the role of glucocorticoids and emphasizes the role of renal factors in the mechanism of the long-term blood pressure changes.

Viral hepatitis--a primer. 2. Prevention and control.

The clinical differentiation of hepatitis A from hepatitis B is often impossible, and only a finding of hepatitis B surface antigen in blood allows the presence of hepatitis B to be definitely diagnosed. Heaptitis A is most easily contracted via the fecal-oral route, while hepatitis B is usually transmitted percutaneously, especially by inoculation with contaminated instruments. Because viral hepatitis has a long incubation period, controlling its spread is difficult. Prevention and control have traditionally depended on general public health measures, and for hepatitis A, passive immunization with immune serum globulin. Promising research is now being conducted to develop vaccines for both active and passive immunization against hepatitis B.

Renal handling of human beta2-microglobulin in the rat: the importance of sham-operation.

The plasma disappearance rates of human beta2-microglobulin and (hydroxy-methyl-C14)-inulin was measured in unoperated, sham-operated, ureter-ligated and nephrectomised rats. Judging from the C14-activity curves in ureter-ligated and nephrectomised rats a substantial glomerular filtration continued after obstruction of the urine flow. Almost 90% of the injected protein had disappeared from plasma 120 min after injection into nephrectomised rats indicating a considerable extra-renal elimination and invalidating attempts to evaluate different renal mechanisms of elimination before and after ureter-ligation. Sham-operation induced an increase of the plasma disappearance of both beta2-microglobulin and inulin. The latter phenomenon may explain earlier findings of similarity between the disappearance curves of low molecular weight proteins in unoperated and ureter-ligated animals and stresses the importance of using sham-operated animals as controls.