Child Abuse and Neglect and its Psycho-Physical and Social Consequences: A Review of the Literature.

Child maltreatment is a complex life experience occurs when a parent or caregiver does an intentional or potential damage to a child, including acts of commission and omission. Child abuse is not an uncommon event, but it is not always recognized. Identifying the real number of maltreated children is a challenge because of the large variability in reported prevalence data across studies. Unfortunately, in the United States, it affects 1 in 8 children, by the age of 18 years, annually. Paediatricians may encounter a variety of forms of maltreatment such as neglect, emotional, physical and sexual abuse. These aspects should be recognised, examined and evaluated by employing a systematic approach and focusing on basic needs of children that may not be met. Child maltreatment is a global problem with serious life-long physical and psychological or psychiatric outcomes. It is associated with important economic and social costs (such as physical and mental health, productivity losses, child welfare, criminal justice and special education costs) due to its high prevalence and its long-term and short-term consequences. In the United States, the average cost of nonfatal maltreatment is $210,012 per children and the cost of fatal maltreatment is $1,272,900. General Practitioners are quite prepared to face the problem of child maltreatment: since they have the opportunity to meet several members of the same family, they can detect stressors that put children at risk of maltreatment. All health professionals have the responsibility to protect children from abuse and neglect.

Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator.

Mismanaged protein trafficking by the proteostasis network contributes to several conformational diseases, including cystic fibrosis, the most frequent lethal inherited disease in Caucasians. Proteostasis regulators, as cystamine, enable the beneficial action of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators in ΔF508-CFTR airways beyond drug washout. Here we tested the hypothesis that functional CFTR protein can sustain its own plasma membrane (PM) stability. Depletion or inhibition of wild-type CFTR present in bronchial epithelial cells reduced the availability of the small GTPase Rab5 by causing Rab5 sequestration within the detergent-insoluble protein fraction together with its accumulation in aggresomes. CFTR depletion decreased the recruitment of the Rab5 effector early endosome antigen 1 to endosomes, thus reducing the local generation of phosphatidylinositol-3-phosphate. This diverts recycling of surface proteins, including transferrin receptor and CFTR itself. Inhibiting CFTR function also resulted in its ubiquitination and interaction with SQSTM1/p62 at the PM, favoring its disposal. Addition of cystamine prevented the recycling defect of CFTR by enhancing BECN1 expression and reducing SQSTM1 accumulation. Our results unravel an unexpected link between CFTR protein and function, the latter regulating the levels of CFTR surface expression in a positive feed-forward loop, and highlight CFTR as a pivot of proteostasis in bronchial epithelial cells.

Sterol profiling in red blood cell membranes and plasma of newborns receiving total parenteral nutrition.

BACKGROUND AND OBJECTIVES: Total parenteral nutrition (TPN) is a lifesaving therapy in children with intestinal failure, frequently complicated by liver dysfunction. Plant sterols (phytosterols) of lipid emulsions have been supposed to contribute to cholestasis in TPN-treated children. The present study aimed to evaluate the plasma and red blood cell membrane (RBCM) phytosterol levels in newborns after a short period of TPN. PATIENTS AND METHODS: Phytosterols, cholesterol, and other sterol levels were quantified by gas chromatography-mass spectrometry in 15 healthy control infants, 22 patients after TPN, and 11 patients before TPN. Sterols of lipid emulsions were quantified. RESULTS: Plasma and RBCM phytosterol levels were, respectively, on average 56 micromol/L and 83 micromol/g per protein in patients after TPN, 13 micromol/L and 15 micromol/g per protein in patients before TPN, and 9 micromol/L and 13 micromoL/g per protein in control infants (P < 0.05 for differences). The days of TPN and the total amount of infused lipids correlated significantly with RBCM phytosterol (P < 0.05); correlations for plasma were positive but not significant. No correlation was observed with plasma bilirubin, gamma-glutamyltransferase, or alanine transaminase. CONCLUSIONS: Plasma and RBCM phytosterols increase significantly in newborns after a short period of TPN. Higher phytosterol levels were observed in some patients that could have been due to their individual variability in phytosterol metabolism and/or clearance. A greater accumulation of phytosterols in membranes may induce TPN-related cholestasis.

Mice transgenic for monocyte-tropic HIV type 1 produce infectious virus and display plasma viremia: a new in vivo system for studying the postintegration phase of HIV replication.

To generate an in vivo system for investigating the postintegration phase of HIV-1 replication, mouse lines transgenic for a full-length infectious proviral clone of a monocyte-tropic HIV-1 isolate, HIV-1JR-CSF, were constructed. Leukocytes from two independent JR-CSF transgenic mouse lines produced HIV-1 that infected human PBMCs. Plasma viremia was detected in these mice at levels (mean, >60,000 HIV RNA copies/ml) comparable to those reported for HIV-1-infected individuals. The levels of HIV RNA in these mice increased several-fold after either treatment with the superantigen Staphylococcus enterotoxin B or infection with Mycobacterium tuberculosis. Thus, a provirus encoding a monocyte-tropic HIV-1 strain under the control of its LTR expressed as a transgene in mice can proceed through the postintegration replication phase and produce infectious virus. In addition, the presence of plasma viremia that can be monitored by measuring plasma HIV-1 RNA levels permits these mice to be used to study the impact of different interventions on modulating in vivo HIV-1 production. Therefore, these mice provide a novel manipulable system to investigate the in vivo regulation of HIV-1 production by factors that activate the immune system. Furthermore, this murine system should be useful in delineating the role of human-specific factors in modulating HIV-1 replication and investigating the in vivo therapeutic efficacy of agents that target the postintegration stages of HIV-1 replication.

Chimeric toxins targeted to the human immunodeficiency virus type 1 envelope glycoprotein augment the in vivo activity of combination antiretroviral therapy in thy/liv-SCID-Hu mice.

Highly active antiretroviral therapy (HAART), which combines multiple inhibitors of essential human immunodeficiency virus type 1 (HIV-1) enzymes, induces dramatic and sustained viral load reductions in many people infected with HIV-1. However, reservoirs of infected cells capable of producing replication-competent virus persist even after years of HAART, preventing elimination of infection. CD4-PE40 and 3B3(Fv)-PE38, chimeric toxins designed to target the HIV envelope (Env), represent a complementary class of agents that selectively kill productively infected cells. To investigate whether these Env-targeted toxins might serve as adjuncts to HAART for the elimination of infected cells, we tested their ability to augment HAART efficacy in vivo by using a thy/liv SCID-hu mouse model. CD4-PE40 and 3B3(Fv)-PE38 markedly enhanced the capacity of HAART to suppress acute HIV-1 infection and improved HAART-mediated viral load reduction in mice with established HIV-1 infection. These results represent the first demonstration of in vivo anti-HIV-1 efficacy for Env-targeted toxins and support their potential therapeutic utility in combination with HAART.

Suppression of HIV type 1 replication by a dominant-negative Ets-1 mutant.

Activity of the distal region of the human immunodeficiency virus (HIV-1) long terminal repeat (LTR), which contains binding sites for the Ets-1 and USF-1 proteins, is integral for HIV-1 replication. The Ets-1 and USF-1 proteins play a critical role in the activity of the HIV-1 LTR distal enhancer region, as indicated by the potent dominant negative effect of a mutant Ets-1 lacking trans-activation domains on the transcriptional activity of the LTR. To determine the biological relevance of the Ets-1 and USF-1 proteins in HIV-1 replication, we examined the effect of expression of the dominant-negative mutant of Ets-1 (dnEts-1) on HIV-1 infection of T cells. We demonstrated that expression of dnEts markedly suppressed HIV-1 infection of a T cell line. This finding indicates that formation of a transcriptionaly active USF-1/Ets-1 complex is important in the productive infection of cells by HIV-1, and suggests that inhibition of the interaction between USF-1 and Ets-1 with the HIV-1 LTR may provide a new target for anti-HIV-1 gene therapy.

HIV type 1 infection of human fetal bone marrow cells induces apoptotic changes in hematopoietic precursor cells and suppresses their in vitro differentiation and capacity to engraft SCID mice.

To investigate the mechanism of HIV-1-induced hematopoietic abnormalities, we examined the effect of HIV-1 infection on the in vitro and in vivo behavior of precursor cells obtained from human fetal bone marrow (HFBM). After infection with the monocyte-tropic isolate HIV-1(ADA), HFBM cells displayed a significant decrease in their subsequent in vitro production of precursor cell colonies and a marked impairment in their engraftment of the bone marrow of irradiated SCID mice. By injecting retrovirally tagged, purified human CD34+ cells into HIV-1(ADA)-infected or uninfected human thymic tissue implanted in SCID mice, we demonstrated that HIV-1 infection also inhibited the in vivo differentiation of CD34+ cells into T cells. To determine the mechanism by which HIV-1 suppressed hematopoietic activity, we investigated whether HIV-1 infection induced apoptotic cell death in hematopoietic cells. Multiparameter flow cytometry with FITC-labeled annexin V and propidium iodide demonstrated that infection of the HFBM with monocyte-tropic, but not T cell line-tropic HIV-1, stimulated apoptosis in the CD34+ hematopoietic precursor population. The presence of a TNF-alpha inhibitor during exposure of the HFBM cells to HIV-1 substantially reduced the level of apoptosis of CD34+ cells and significantly decreased the repression of in vitro colony formation induced by HIV-1. However, inhibition of TNF-alpha during HFBM cell culture with HIV-1 did not restore their capacity to engraft SCID mice. Taken together, these results indicated that HIV-1 suppression of human hematopoietic cell maturation is a multifactoral phenomenon, a crucial element of which may be HIV-1-induced apoptosis of precursor cells mediated by TNF-alpha production.

Immunologic responses of HIV-1-infected study subjects to immunization with a mixture of peptide protein derivative-V3 loop peptide conjugates.

V3 loop peptide sequences from several HIV-1 strains were covalently linked to purified protein derivative (PPD) of Mycobacterium tuberculosis. A mixture of PPD conjugates of V3 loop peptides from six different strains of HIV-1 induced a stronger antibody response than a single V3 peptide-conjugate administered to guinea pigs and humans. Sera from animals immunized with a PPD-six peptide-PPD conjugate neutralized multiple primary-isolate strains of HIV-1. Potent immune responses were noted only when animals were primed with bacillus Calmette-Guerin (BCG), PPD was covalently bound to the peptides, and PPD was used as the carrier protein. Based on these animal studies, an immunogen consisting of PPD-conjugated V3 loop peptides from five HIV-1 strains was tested in 7 HIV-1 seropositive PPD skin test positive study subjects. Vaccinees exhibited over time a uniform increase in neutralizing antibodies for both laboratory adapted and primary isolates of HIV-1, including strains from multiple clades. In 3 patients with baseline viral loads between 8000 and 12,000 RNA copies/ml, the viral load declined in 2 patients to <400 copies/ml and in 1 patient to 1200 copies/ml without concurrent administration of highly active antiretroviral therapy (HAART).

Decreased susceptibility of peripheral blood mononuclear cells from individuals heterozygous for a mutant CCR5 allele to HIV infection.

OBJECTIVE: Individuals homozygous for a deletion in the CCR5 gene (CCR5delta32/CCR5delta32) are resistant to HIV infection, indicating that this particular chemokine receptor plays a crucial role in the initiation of in vivo HIV infection. We investigated the effect of the heterozygote genotype (CCR5/CCR5delta32) on susceptibility of peripheral blood mononuclear cells (PBMC) to HIV infection. DESIGN: Sensitivity to HIV infection of PBMC from volunteers with either the CCR5/CCR5, CCR5/CCR5delta32, or CCR5delta32/CCR5delta32 genotypes was examined by challenging their PBMCs with serial titers of HIV isolates with different cellular tropisms. The genotype of the PBMCs was correlated with the lowest viral inoculum required to initiate productive infection with either three M-tropic HIV-1 isolates, (92RW009A, HIV-1ada, and HIV-1(59)), one dual-tropic HIV-1 isolate (92BR021), or two T-tropic HIV-1 isolates (92UG021 and 92UG029). RESULTS: PBMCs from the CCR5/CCR5delta32 group required a significantly higher inoculum (p value from .036 to .003) to become infected with these three M-tropic HIV-1 isolates than did PBMC from the CCR5/CCR5 group, but became infected after exposure to an inoculum of T-tropic HIV-1 isolates that was comparable to that which infected PBMCs from the CCR5/CCR5 individuals. CONCLUSIONS: The decreased susceptibility of PBMCs from individuals heterozygous for the CCR5 deletion to HIV infection by M-tropic HIV-1 isolates may provide a mechanistic explanation for the delayed progression of disease in some CCR5/CCR5delta32 individuals.

thy/liv-SCID-hu mice: a system for investigating the in vivo effects of multidrug therapy on plasma viremia and human immunodeficiency virus replication in lymphoid tissues.

Modified, human immunodeficiency virus (HIV)-inoculated thy/liv-SCID-hu mice were used to evaluate the in vivo efficacy of antiretroviral drugs. Ritonavir treatment alone initially suppressed plasma viremia, but the viremia recurred with the appearance of ritonavir-resistant HIV isolates. Multidrug therapy suppressed plasma HIV RNA to undetectable levels; however, plasma viremia returned after therapy was stopped, showing that the therapy did not completely suppress HIV infection in the thymic implant. When thy/liv-SCID-hu mice were treated with a combination of zidovudine, lamivudine, and ritonavir immediately after inoculation with HIV, cocultures of the thymic implants remained negative for HIV even 1 month after therapy was discontinued, suggesting that acute treatment can prevent the establishment of HIV infection. Thus, these modified thy/liv-SCID-hu mice should prove to be a useful system for evaluating the effectiveness of different antiretroviral therapies on acute and chronic HIV infection.

Thy/Liv-SCID-Hu mice implanted with human intestine: an in vivo model for investigation of mucosal transmission of HIV.

Mucosal transmission is a major route by which individuals become infected with HIV. Investigation into the mechanism by which mucosal transmission of HIV occurs would be greatly facilitated by the development of a small animal model infectible with HIV by the mucosal route. We have previously described a SCID-hu mouse model, in which human thymic and liver tissues are implanted under both kidney capsules (thy/liv-SCID-hu mice), which are populated in the periphery with high numbers of human T cells and that develop disseminated HIV-1 infection after intraperitoneal injection. To expand further the usefulness of the thy/liv-SCID-hu mouse as a model for studying mucosal transmission of HIV, thy/liv-SCID-hu mice were subcutaneously implanted with human intestinal tissue in a manner that maintained the lumen. Four months later, the histological appearance of the implanted intestine resembled that of normal human bowel tissue and the lamina propria was populated with human T cells. Six weeks after introduction of HIV into the lumen of the intestinal implant, the mice developed disseminated HIV infection. Scattered HIV-infected cells were detected in the lamina propria of the implant, indicating that HIV infection in these mice was mediated by transmission of the virus across the mucosa of the human intestinal implant. Thus, our modified thy/liv-SCID-hu mice transplanted with human bowel tissue should provide a novel model for investigating mucosal transmission of HIV.

Saquinavir-mediated inhibition of human immunodeficiency virus (HIV) infection in SCID mice implanted with human fetal thymus and liver tissue: an in vivo model for evaluating the effect of drug therapy on HIV infection in lymphoid tissues.

Treatment with protease inhibitors alone or in combination with inhibitors of reverse transcriptase potently suppresses levels of human immunodeficiency virus (HIV) RNA in plasma and thereby may significantly delay the progression of HIV-mediated disease. To investigate the effect of treatment with the protease inhibitor saquinavir on HIV replication in the lymphoid tissues, we used a SCID-hu mouse model that we developed, in which human thymic and liver tissues (hu-thy/liv) were implanted under both kidney capsules in SCID mice (thy/liv-SCID-hu mice). These mice are populated in the periphery with large numbers of human T cells and develop disseminated HIV infection after intraimplant injection. thy/liv-SCID-hu mice with established HIV infection that were treated for 1 month with saquinavir had a significantly lower viral load present in the implanted hu-thy/liv and mouse spleen than did the untreated HIV-infected thy/liv-SCID-hu mice. To examine the capacity of acute treatment with saquinavir to prevent HIV infection, some thy/liv-SCID-hu mice were inoculated with HIV and then immediately started on saquinavir. Although treated mice had markedly lower viral loads in the thy/liv implants and spleens, HIV infection was not completely prevented. Thus, the effect of antiviral therapy on HIV infection in the major site of HIV replication, the lymphoid tissues, can be readily evaluated in our thy/liv-SCID-hu mice. These mice should prove to be a useful model for determining the in vivo effectiveness of different therapeutic interventions on acute and chronic HIV infection.

Treatment of visceral leishmaniasis in children with liposomal amphotericin B.

We used liposomal amphotericin B as first-choice treatment of visceral leishmaniasis in 106 immunocompetent children who acquired the infection in a temperate region of southern Europe (Italy) where Leishmania infantum visceral leishmaniasis is endemic. The aim of the study was to identify the minimum total dose of liposomal amphotericin B needed to cure the infection in children and reduce the period of hospitalization. We conclude that the optimal regimen in immunocompetent children with L. infantum visceral leishmaniasis to be a total dose of 18 mg/kg of liposomal amphotericin B (3 mg/kg per day for 5 days, followed by 3 mg/kg administered as an outpatient regimen on day 10).

Mice transgenic for human CD4 and CCR5 are susceptible to HIV infection.

HIV entry into human cells is mediated by CD4 acting in concert with one of several members of the chemokine receptor superfamily. The resistance to HIV infection observed in individuals with defective CCR5 alleles indicated that this particular chemokine receptor plays a crucial role in the initiation of in vivo HIV infection. Expression of human CD4 transgene does not render mice susceptible to HIV infection because of structural differences between human and mouse CCR5. To ascertain whether expression of human CD4 and CCR5 is sufficient to make murine T lymphocytes susceptible to HIV infection, the lck promoter was used to direct the T cell-specific expression of human CD4 and CCR5 in transgenic mice. Peripheral blood mononuclear cells and splenocytes isolated from these mice expressed human CD4 and CCR5 and were infectible with selected M-tropic HIV isolates. After in vivo inoculation, HIV-infected cells were detected by DNA PCR in the spleen and lymph nodes of these transgenic mice, but HIV could not be cultured from these cells. This indicated that although transgenic expression of human CD4 and CCR5 permitted entry of HIV into the mouse cells, significant HIV infection was prevented by other blocks to HIV replication present in mouse cells. In addition to providing in vivo verification for the important role of CCR5 in T lymphocyte HIV infection, these transgenic mice represent a new in vivo model for understanding HIV pathogenesis by delineating species-specific cellular factors required for productive in vivo HIV infection. These mice should also prove useful for the assessment of potential therapeutic and preventative modalities, particularly vaccines.

SCID-hu mice: a model for studying disseminated HIV infection.

Modifications that we introduced into the implantation of human fetal thymus and liver into SCID mice (thy/liv-SCID-hu mice) markedly increased the population of human T cells and monocytes present in the peripheral blood and peripheral lymphoid compartment of these mice. As a result, the modified thy/liv-SCID-hu mice developed disseminated HIV infection after intraimplant or i.p. inoculation. After chronic HIV infection of these mice, depletion of the peripheral human T cells was observed as reported in HIV-infected individuals. In addition, these mice also developed plasma viremia after infection with HIV. The peripheral blood mononuclear cells were responsive to in-vivo cytokine regulation as evidenced by induction of human IFN-gamma gene expression by human IL-12 and inhibition by human IL-10. Acute treatment with human IL-10 but not with human IL-12 inhibited the development of plasma viremia and HIV infection in thy/liv-SCID-hu mice inoculated with HIV-1(59), a clinical isolate. SCID mice transplanted with cultured human fetal bone marrow displayed significant engraftment of the mouse bone marrow with human precursor cells and population of the peripheral blood with human B cells and monocytes. The peripheral blood of these bone marrow-transplanted SCID mice also became populated with human T cells after they were implanted with human thymic tissue due to migration of human precursor cells from the mouse bone marrow to the implanted human thymus. Thus, these modified SCID-hu mice should prove to be a valuable in-vivo model for studying the immunopathogenesis of HIV infection and for examining the in-vivo efficacy of immunomodulatory, drug and gene therapy in modifying HIV infection.

Inhibition of acute in vivo human immunodeficiency virus infection by human interleukin 10 treatment of SCID mice implanted with human fetal thymus and liver.

To improve the usefulness of in vivo mode for the investigation of the pathophysiology of human immunodeficiency virus (HIV) infection, we modified the construction of SCID mice implanted with human fetal thymus and liver (thy/liv-SCID-hu mice) so that the peripheral blood of the mice contained significant numbers of human monocytes and T cells. After inoculation with HIV-1(59), a primary patient isolate capable of infecting monocytes and T cells, the modified thy/liv-SCID-hu mice developed disseminated HIV infection that was associated with plasma viremia. The development of plasma viremia and HIV infection in thy/liv-SCID-hu mice inoculated with HIV-1(59) was inhibited by acute treatment with human interleukin (IL) 10 but not with human IL-12. The human peripheral blood mononuclear cells in these modified thy/liv-SCID-hu mice were responsive to in vivo treatment with exogenous cytokines. Human interferon gamma expression in the circulating human peripheral blood mononuclear cells was induced by treatment with IL-12 and inhibited by treatment with IL-10. Thus, these modified thy/liv-SCID-hu mice should prove to be a valuable in vivo model for examining the role of immunomodulatory therapy in modifying HIV infection. Furthermore, our demonstration of the vivo inhibitory effect of IL-10 on acute HIV infection suggests that further studies may be warranted to evaluate whether there is a role for IL-10 therapy in preventing HIV infection in individuals soon after exposure to HIV such as for children born to HIV-infected mothers.

Hansenula anomala killer toxin induces secretion and severe acute injury in the rat intestine.

BACKGROUND & AIMS: The yeast Hansenula anomala has been associated with gastrointestinal symptomatology and damage to the intestinal wall in humans. In vitro and in vivo, H. anomala secretes a toxin, killer toxin, which is lethal to other microorganisms. In view of the very high rate of killer phenotype expression recorded for H. anomala strains in nature, this study aimed to investigate the hypothesis that H. anomala killer toxin plays a role in the pathogenesis of H. anomala-induced enteritis. METHODS: Effects of active and heat-inactivated H. anomala killer toxin on intestinal fluid homeostasis and electrolyte balance were investigated in rat small intestine using a standard intestinal perfusion technique. Sections of the perfused jejunum tracts were examined histologically. RESULTS: H. anomala killer toxin induced a significant secretion of water and electrolytes. No significant change was observed when either heat-inactivated H. anomala killer toxin or control growth medium were tested. Histological analysis showed ischemic degeneration of villi and sloughing of surface epithelium in 50% of active H. anomala killer toxin-perfused jejuna. CONCLUSIONS: This paper presents original observations compatible with the hypothesis that H. anomala killer toxin plays a role in the pathogenesis of H. anomala-induced enteritis.

Asymptomatic carriage of intestinal Cryptosporidium in immunocompetent and immunodeficient children: a prospective study.

Little information is available on asymptomatic carriage of Cryptosporidium in immunocompetent and immunodeficient children. We prospectively studied a group of asymptomatic children, 78 immunocompetent and 50 immunodeficient, to document the incidence of asymptomatic carriage of cryptosporidiosis in such a population. We also investigated whether the treatment of children who carried asymptomatic cryptosporidiosis could help in reducing their risk of gastrointestinal symptoms as well as the shedding of infectious oocysts. The occurrence of multiple infections with common intestinal pathogens including Giardia lamblia was also investigated. Asymptomatic cryptosporidiosis was documented in 6.4% of immunocompetent and 22% of immunodeficient children. In a control symptomatic population Cryptosporidium was found in 4.4% of immunocompetent and 4.8% of immunodeficient children. Asymptomatic carriage of Cryptosporidium was documented in 2 human immunodeficiency virus-infected children, one of whom also carried Giardia asymptomatically. Treatment with spiramycin (100 mg/kg daily for 14 days) reduced significantly the duration of the shedding of potentially infectious oocysts. Finally no gastrointestinal symptoms developed in children treated for asymptomatic infection with Cryptosporidium, whereas children who were not treated developed gastrointestinal symptoms.

Safety and immunogenicity of a V3 loop synthetic peptide conjugated to purified protein derivative in HIV-seronegative volunteers.

OBJECTIVES: To develop a peptide-based model for a preventive vaccine for HIV-1 infection. DESIGN: Phase I trial in HIV-1-seronegative volunteers. PARTICIPANTS: Adult healthy subjects HIV-1-antibody-seronegative in an enzyme-linked immunosorbent assay, screened for tuberculin [purified protein derivative (PPD)] reactivity with 2 tuberculin units PPD-administered intradermally. INTERVENTIONS: Submicrogram doses of a PPD conjugate with a peptide of the primary neutralizing domain (PND) of HIV-1MN (PPD-MN-PND) were administered intradermally to tuberculin skin-test-positive and -negative volunteers. RESULTS: Antibodies to the MN-PND were measured after two immunizations in 10 out of 11 PPD skin-test-positive volunteers. After the fourth immunization high-affinity antibodies were detected, which persisted for over 1 year. High titers of MN-PND-specific immunoglobulin (Ig) G and IgA were detected in the serum and saliva of all volunteers tested. Serum antibodies were cross-reactive with PND peptide from some other HIV-1 strains but neutralized only the HIV-1MN prototype. Human leukocyte antigen (HLA)-B7-restricted MN-PND-specific cytotoxic T lymphocytes (CTL) were also detected. CONCLUSIONS: The PPD-MN-PND vaccine at submicrogram doses is safe and immunogenic in PPD skin-test-positive healthy adult volunteers. Long lasting humoral immune responses in the serum and saliva were possibly accompanied by HLA-B7-restricted CTL responses. This is a vaccine prototype that can be rapidly and inexpensively modified to include other peptide epitopes. It is especially suitable for use in a worldwide multibillion Bacillus Calmette-Guérin (BCG)-primed or tuberculosis-exposed population at risk for HIV-1 infection.

Prospective study of lactose absorption during cancer chemotherapy: feasibility of a yogurt-supplemented diet in lactose malabsorbers.

Chemotherapy is a recognized cause of morphological alterations to the proximal intestine. Lactose malabsorption, the functional consequence of a small intestinal enzymatic derangement, has been shown to play an important role in causing gastrointestinal symptoms in subjects receiving chemotherapy. To establish a rational basis for the exclusion of lactose from the diet and to reduce the risk of developing gastrointestinal symptoms, we conducted a study of lactose absorption in 20 children during cancer chemotherapy. Because lactose is an important nutritional sugar, the tolerance of lactose provided by yogurt was examined. Lactose absorption was investigated by a hydrogen breath test (BT) after oral ingestion of milk (250 ml) containing physiological doses of lactose (12 g). The effect of yogurt supplementation was also tested by BT after meals of yogurt (450 g) also containing physiological doses of lactose (12.1 g). In 11 children, lactose malabsorption was detected by BT during the study before any gastrointestinal symptom revealed this status. Of these 11 children, no gastrointestinal discomfort developed in five receiving a lactose-excluded diet. In contrast, in the six children not restricted in lactose intake, gastrointestinal symptoms were observed 4 to 13 weeks after lactose malabsorption was detected by BT. The findings of our study suggested the usefulness of dietary supplementation with yogurt, a lactose-containing food, in children who developed lactose malabsorption. In fact, all lactose-malabsorbent children showed good lactose absorption and tolerance when tested by yogurt BT.(ABSTRACT TRUNCATED AT 250 WORDS)