The prioritisation of paediatrics and palliative care in cancer control plans in Africa.

BACKGROUND: Given the burden of childhood cancer and palliative care need in Africa, this paper investigated the paediatric and palliative care elements in cancer control plans. METHODS: We conducted a comparative content analysis of accessible national cancer control plans in Africa, using a health systems perspective attentive to context, development, scope, and monitoring/evaluation. Burden estimates were derived from World Bank, World Health Organisation, and Worldwide Palliative Care Alliance. RESULTS: Eighteen national plans and one Africa-wide plan (10 English, 9 French) were accessible, representing 9 low-, 4 lower-middle-, and 5 upper-middle-income settings. Ten plans discussed cancer control in the context of noncommunicable diseases. Paediatric cancer was mentioned in 7 national plans, representing 5127 children, or 13% of the estimated continental burden for children aged 0-14 years. Palliative care needs were recognised in 11 national plans, representing 157 490 children, or 24% of the estimated Africa-wide burden for children aged 0-14 years; four plans specified paediatric palliative needs. Palliative care was itemised in four budgets. Sample indicators and equity measures were identified, including those highlighting contextual needs for treatment access and completion. CONCLUSIONS: Recognising explicit strategies and funding for paediatric and palliative services may guide prioritised cancer control efforts in resource-limited settings.

Platelet-rich plasma for zone II flexor tendon repair.

BACKGROUND: Platelet-rich plasma (PRP) has shown promise in the treatment of tendinopathy, including rotator cuff and lateral epicondylitis. Here, we evaluate the effect of PRP on healing in a rabbit zone II flexor tendon model. METHODS: Thirty New Zealand white rabbits underwent transection and repair of the second and fourth flexor digitorum profundus. Half of the rabbits received autologous PRP intraoperatively, while the other half underwent standard four-strand tendon repair. Tendons were examined at 2, 4, and 8 weeks postoperatively. Range of motion and ultimate tensile strength were assessed on the fourth toes, while second toes underwent histologic analysis with hematoxylin and eosin, Masson Trichrome, and Picrosirius Red, for assessment of cell count, collagen content, and collagen maturity. RESULTS: There were no significant differences in ultimate tensile strength between treatments at 2, 4, or 8 weeks. There was a trend towards lower tensile strength in the PRP group at 2 weeks. There was no statistically significant difference in excursion or range of motion between PRP and control tendons. Cell counts at 4 weeks were statistically significantly reduced in the PRP tendons as compared to controls. No difference in collagen content or maturity was detected. CONCLUSIONS: In contrast to previous studies, PRP did not significantly improve ultimate tensile strength. PRP-treated tendons exhibited trends towards reduced healing, including a significant reduction in cell counts as well as a smaller increase in collagen deposition over time as compared to controls. Further study is needed to determine the precise effect of PRP on intrasynovial flexor tendon repairs.

cDNA cloning, sequencing and characterization of bovine pim-1.

The cDNA clone of bovine pim-1 has been isolated from phorbol-12-myristate-13-acetate (PMA) and concanavalin A (ConA)-activated peripheral blood lymphocytes (PBLs). The full-length cDNA contains a 411bp 5' untranslated region (5'-UTR), followed by a 939bp coding region and a 3' untranslated region (3'-UTR) that contains 1403bp. Comparison of the bovine pim-1 coding sequence with the human, rat, mouse, frog and zebrafish counterparts reveals 94, 90, 89, 67 and 40% homology at the nucleotide level, respectively. The predicted amino acid sequence of bovine Pim-1 shares 98.7, 97.1, 93.3, 68.8, and 52.4% similarity with the sequences of human, rat, mouse, frog, and zebrafish, respectively. The 5'-UTR of bovine pim-1 shares high sequence similarity to the human and mouse counterparts and is G/C-rich (75%) which may promote a high degree of secondary structure. The 3'-UTR of bovine pim-1 contains two potential polyadenylation sites and an A/T-rich motif which has been shown to decrease the stability of polyA mRNA molecules. Southern blot results indicate that a single copy of the gene exists in the bovine genome. Northern blot results show that PMA stimulation of PBLs increases the expression of the pim-1 mRNA. In addition, examination of Pim-1 protein expression in PBLs stimulated with a variety of mitogens including ConA, PMA, anti-CD3 and purified protein derivative (PPD) from Mycobacterium tuberculosis, reveals two different types of expression patterns during the course of a 24h period of stimulation. ConA and PPD gave a biphasic pattern of expression while PMA and anti-CD3 gave single transient pattern of expression suggesting that expression is controlled by more than one signaling pathway.

N-methyl-D-aspartate-stimulated increases in intracellular calcium exhibit brain regional differences in sensitivity to inhibition by ethanol.

This study compared N-methyl-D-aspartate (NMDA)-stimulated increases in intracellular calcium in fura-2-loaded neurons dissociated from newborn rat brainstem (EC50 in microM; 6.4), cerebellum (9.5), forebrain (6.3), and hippocampus (10.6). Ethanol inhibition of the response to 25 microM NMDA differed among the regions. The NMDA response in hippocampus was inhibited by 20 mM ethanol; cortex and cerebellum responses were inhibited by 80 mM ethanol, and no inhibition was seen in the brainstem. Addition of glycine (15 microM) failed to attenuate ethanol inhibition of the NMDA response. These results demonstrate that ethanol inhibition of NMDA-stimulated responses varies according to brain region. In contrast to previous findings from this laboratory using dissociated neurons from whole brain, the addition of glycine did not reverse the inhibitory effects of ethanol on NMDA-stimulated responses.

Effects of in vitro ethanol and fetal ethanol exposure on glutathione stimulation of N-methyl-D-aspartate receptor function.

The present studies investigated the effects of glutathione (GSH; gamma-glutamylcysteinylglycine) and its oxidized form (GSSG) on neuronal N-methyl-D-aspartate (NMDA) receptor activation in both acute and chronic preparations of ethanol exposure. It was demonstrated using fura-2-loaded dissociated brain cells from newborn rat pups that both GSH and GSSG (0-4 mM) produced concentration-dependent increases in intracellular calcium similar to those produced by NMDA and other agonists of the NMDA receptor. GSH-stimulated calcium entry was not inhibited by low intoxicating concentrations of ethanol, which contrasts with ethanol's typical inhibitory effect on NMDA-stimulated receptor activation. Behavioral studies in adult rats demonstrated that ethanol-induced sleep times were significantly decreased when 10 microliters of GSSG (20 mM) were administered intracerebroventricularly approximately 5 min before an intraperitoneal injection of 20% (w/v) ethanol (3 g/kg). These findings suggest that the less potent effect of ethanol on GSH-stimulated calcium entry as well as the reduction in ethanol-induced sleep times may be related to the presence of glycine in the peptide. The glycine found in GSH may activate the glycine site and block or reduce ethanol's action on this site. It appears that although GSH may play an important role in the activation of the NMDA receptor, this action does not involve a process that is sensitive to acute ethanol exposure. In contrast, when rat pups were chronically exposed to ethanol via prenatal exposure before the fura-2 preparation, increases in NMDA- and GSH-stimulated calcium entry were significantly decreased relative to those in pair-fed and ad libitum-fed controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Low HIV-1 proviral DNA burden detected by negative polymerase chain reaction in seropositive individuals correlates with slower disease progression.

During 1989, 316 members of a cohort of homosexual men were tested for HIV-specific DNA by the polymerase chain reaction (PCR) using a pair of gag-region primers. Of 125 HIV-seronegative subjects, 123 (98.4%) were PCR-negative while 158 (82.7%) of 191 HIV-seropositive subjects were PCR-positive. Fewer of the 33 subjects who were seropositive and PCR-negative were at Centers for Disease Control (CDC) stage IV than the seropositive, PCR-positive subjects (6 versus 25%; P = 0.030). The seropositive, PCR-negative group had higher mean CD4 counts (640 versus 490 x 10(6) cells/l; P = 0.006), higher CD4: CD8 ratios (0.92 versus 0.64; P = 0.004), lower immunoglobulin (Ig) G levels (1290 versus 1645 mg/dl; P = 0.002), lower IgA levels (168 versus 251 mg/dl; P less than 0.001), and lower C1q binding activity (8 versus 14%; P = 0.010) than the seropositive, PCR-positive subjects. The median rate of CD4 cell decline in the 3 years preceding the PCR sample was less marked in the seropositive, PCR-negative group than the seropositive, PCR-positive group (-58 versus -77 x 10(6) cells/l per year; P = 0.028). To control for duration of infection, we restricted the analysis to the subgroups of 11 seropositive, PCR-negative subjects and 34 seropositive, PCR-positive subjects who had seroconverted earlier in the cohort study. Both subgroups had similar durations of infection, yet the same pattern of differences persisted.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of serotonergic drugs on negative contrast in consummatory behavior.

The effect of acute and chronic administration of the 5-HT1A agonist buspirone on successive negative contrast was investigated in Experiments 1-6. Contrast in consummatory behavior was induced by shifting rats from a 32% to a 4% sucrose solution. Experiments 1-5 showed that buspirone (0.125, 0.25, 0.5, 1.0, 2.0, 15.0 mg/kg) was ineffective in alleviating contrast or in facilitating recovery from contrast. The 15 mg/kg dose substantially decreased consummatory responding. Experiment 6 showed that the chronic (24 days) administration of buspirone (0.5, 2.0 mg/kg) also did not alleviate contrast. The chronic, but not the acute administration of the 2.0 mg/kg dose decreased consummatory behavior. In Experiment 7 the 5-HT1A agonist gepirone (2.5, 5.0 and 10.0 mg/kg) was also found to be ineffective in reducing contrast but, at the higher doses, decreased overall sucrose intake. Experiments 8 and 9 found that the 5-HT2 antagonists ketanserin (2.0 and 8.0 mg/kg) and ritanserin (0.63 and 2.5 mg/kg) also did not alleviate contrast. Midazolam (1.0 mg/kg), included as a positive control, eliminated contrast. These data suggest that serotonergic mechanisms are not involved in negative contrast.

Distribution of antibodies against denatured collagen in AIDS risk groups and homosexual AIDS patients suggests a link between autoimmunity and the immunopathogenesis of AIDS.

Autoimmunity often precedes the onset of AIDS-related complex or AIDS, and a number of autoantibodies have been described in AIDS patients and persons at risk for AIDS. The presence of such antibodies provokes speculation that autoimmunity is a component of AIDS pathogenesis. We report evidence of an autoantibody (anticollagen) common to all homosexual AIDS patients studied. High titer serum reactivity against collagen was detected in all homosexual AIDS patients, and in HIV+ homosexuals (66%), HIV+ i.v. drug users (38%) HIV- homosexuals (32%), HIV+ transfusion recipients (22%), and HIV+ hemophiliacs (13%), but not in HIV- i.v. drug users, HIV- transfusion recipients, HIV- hemophiliacs, rheumatoid arthritis patients, or controls. Anticollagen reactivity does not correlate with serum IgG levels, so it is not merely a reflection of polyclonal B-cell activation. Titration of anticollagen positive sera typically revealed anticollagen antibody titers 100 times those of normal sera. Affinity purification and immunoblot analysis confirmed the antibody nature of the anticollagen reactivity. The anticollagen antibodies react preferentially with primary determinants of types I and III collagen revealed after heat denaturation. Similar antibodies occur infrequently in rheumatoid arthritis patients, more often on SLE, and frequently in graft vs host disease and lepromatous leprosy. Levels of anticollagen activity in HIV+ i.v. drug users and transfusion recipients correlate with serum beta 2-microglobulin levels, suggesting that those persons with anticollagen antibodies are at greater risk of developing AIDS. This correlation, the fact that anticollagen antibodies occurred in all homosexual AIDS patients tested, and the occurrence of antibodies against denatured collagen in immune disorders with features similar to AIDS suggest these antibodies may be related to disease progression. The association of anticollagen autoantibodies with AIDS and certain other infections and immune disorders may reflect common immunopathogenic features in the etiology of these disorders.

Progression to AIDS and predictors of AIDS in seroprevalent and seroincident cohorts of homosexual men.

As part of an ongoing prospective study of seropositive homosexual men in Vancouver, Canada, a seroprevalent cohort of 246 subjects (i.e. duration of infection unknown) and a seroincident cohort of 102 subjects (i.e. duration of infection known) were followed a median of 63 and 45 months, respectively. Follow-up with validation utilizing record linkage with the Canadian Federal Centre for AIDS registry revealed 58 and nine cases of AIDS in the seroprevalent and seroincident cohorts, respectively, through July 1988. These data yield product limit estimates of the cumulative progression rates to AIDS at 60 months of 23.0% for the seroprevalent cohort, 13.0% for the seroincident cohort, and 21.0% for the combined groups. Univariate analyses revealed the following to be statistically and clinically significant predictors of AIDS progression: low CD4 counts, low CD4/CD8 ratios, elevated immune complexes, elevated immunoglobulin G (IgG) and immunoglobulin A (IgA) levels, and low platelet counts. Cox regression revealed that elevated IgA levels, low CD4 counts, elevated immune complexes, two or more symptoms, and more than 20 male sexual partners in high-risk areas in the 5 years prior to enrollment were independent predictors of progression to AIDS over the subsequent 5 years. A multivariate risk function based on the latter five variables delineated low-, medium- and high-risk groups whose 5-year progression rates to AIDS were 6.7, 15.6 and 64.4%, respectively. The high-risk group contained 75% of all subjects who progressed to AIDS. Only 6% of the high-risk group would have qualified for zidovudine therapy under current guidelines at the beginning of the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that prior immune dysfunction predisposes to human immunodeficiency virus infection in homosexual men.

To investigate the role of host susceptibility to HIV-1 infection, we studied subsequent seroconversion in 161 individuals, initially seronegative to HIV-1, who underwent skin testing for cutaneous anergy at an index visit within a prospective study of homosexual men. There were 23 seroconversions in these men by 45 months following the skin testing, yielding a crude rate of seroconversion of 14.3%. While results of purified protein derivative (PPD), Candida, and Trichophyton skin tests were not associated with subsequent course, anergy to dinitrochlorobenzene (DNCB) was predictive of subsequent seroconversion. Kaplan-Meier estimates for the risk of seroconversion during 45 months of follow-up in those men initially anergic and reactive to DNCB were 28.9 and 11.1%, respectively, yielding a relative risk of 2.6 (p = 0.006). The estimated relative risk was stable with adjustment by Cox regression for annual number of male sexual partners and frequency of receptive anal intercourse, and was not sensitive to various changes in the definition of seroconversion time and of eligibility criteria. These data suggest that an impaired host immune status may be associated with an increased risk of HIV-1 infection that is independent of risk of exposure to the virus, supporting earlier speculations that HIV-1 may itself be opportunistic. The notion of varying host susceptibility to infection, at least with regard to sexual transmission in homosexual men, may help to explain the frequent observation of individuals who have been repeatedly exposed to the virus and yet have remained uninfected.

Identification of a T cell subset using a rabbit antibody raised against a T suppressor molecule.

Rabbit antiserum to a unique component of an Ag-binding Ts-factor was generated by repeated immunization with purified 30-kDa protein isolated from Fd11 Ts factor (11). This antiserum (anti-p30) was shown to recognize cell surface determinants expressed on the Ts hybridomas Fd11 and A10 but not the fusion partner BW5147. Furthermore, this antiserum was shown to bind to approximately 4% of thymocytes and 10% of nylon wool-purified splenic T cells from all strains of mice tested. Sorting nylon wool-purified T cells from DBA/2 mice for the CD4+ and CD8+ subsets revealed both populations contained cells that bound anti-p30. In addition, when CD4-8- thymocytes were examined for anti-p30 labeling, it was found that about 30% of this enriched population also expressed p30 molecules. In a functional study, anti-p30 was able to neutralize the suppressive effects of Fd11 on a specific assay for in vitro antibody synthesis against ferredoxin.

Utilization of odor cues as a function of reward-magnitude contrast and delay of reinforcement.

An experiment manipulating both reward-magnitude contrast and delay of reinforcement is reported. The results indicated that odor cues are produced under conditions of delayed large-reward versus nonreward contrast but not under large- versus small-reward contrast. Additional magnitude and delay manipulations that resulted in the elimination of odor-based double-alternation patterning in the straight runway are presented.

Taste preference of the adult rat as a function of prenatal exposure to ethanol.

Two groups of pregnant rats (n = 10) received exposure to either 10% ethanol or water. All male offspring (n = 43) received a six-day preference test (ethanol vs water) at 90 days of age. Fluid consumption scores indicated a significant preference for water by all Ss. However, those animals receiving prenatal ethanol exposure consumed significantly more ethanol during preference testing than did the animals receiving prenatal water exposure.

Shock-elicited aggression as a function of early ethanol exposure.

Upon reaching maturity the offspring (N = 88) of animals exposed during pregnancy to ethanol and plain water, respectively, served as Ss in a shock-elicited aggression test. Significantly higher levels of aggression were shown by those animals that had received prenatal ethanol exposure. Several ethanol-related birth effects were also noted.

Effect of rhythmic grouping on stream segregation.

Three experiments investigated the role of temporal grouping on auditory stream segregation. For sounds that formed frequency streams (e.g., 400 Hz, 500 Hz, 1600 Hz, and 2000 Hz), the effect of rhythm was minimal. Temporal grouping did not affect judgments of stream segregation and did not affect difficulty of sequence identification. In contrast, for sounds that tended to form one coherent sequence (e.g., 750 Hz, 1500 Hz, 3000 Hz, and 6000 Hz), temporal grouping affected judgments of stream segregation as well as difficulty of identification. The temporal grouping could space the three lower or three higher pitch tones equally in time and this induced isochronous stream segregation. Subjects could not interleave the resulting streams, and identification became far more difficult. The role of rhythmic grouping is therefore contextual, depending on the relationships between the elements as well as the order of the elements.

Shock-elicited aggression as a function of acute and chronic ethanol challenges.

In a test of competing hypotheses regarding the effects of alcohol on shock-elicited aggression, animals maintained on a food restricted regimen were administered either chronic or acute ethanol challenges. Chronic Ss showed a significantly higher rate of target-directed aggression and spent significantly more time in aggressive activity than did acute or saline control animals. Results support the proposed interactive effect of food restriction and extended periods of alcohol intake leading to increased aggression.

The immune response to ferredoxin: characterization of a major idiotype in serum using monoclonal antibody derived by cell fusion.

Ferredoxin (Fd) is a low mol. wt protein (6000 d) isolated from Clostridium pasteurianum. This antigen possess two non-cross-reactive antigenic determinants and engenders a restricted antibody response in selected strains of mice. Immunochemical studies of Fd have shown that antibody responses are confined to two sequences of between five and seven amino acids in extent located at the NH2-and COOH-termini of the molecule. Serum antibodies from responder strains of mice bind these epitopes in proportions which are regulated by genes mapping in the Ir-region of the H-2 complex. A hybrid cell line secreting monoclonal Fd-binding antibody has been isolated from an immune mouse through fusion with the SP2/0 myeloma cell line. The resulting antibody binds to a single determinant located at the nH2-terminal of the molecule. An anti-idiotype antibody to this monoclonal antibody was raised in rabbits. After appropriate absorptions, its specificity for the paratopic regions of the hybridoma antibody was established by demonstrating its displacement from reaction with the idiotype by Fd. Analysis of the distribution of the hybridoma idiotype in serum antibodies from congenic mouse strains indicates that it is a major idiotype expressed in different inbred strains sharing identity at the Igh-1 locus.