Growth, morbidity, and mortality in a cohort of institutionalized HIV-1-infected African children

OBJECTIVE: As a result of the HIV epidemic in Africa, much debate exists on whether institutionalized compared with community-based care provides optimum management of infected children. Previous reports calculated 89% mortality by age 3 years among outpatients in Malawi. No similar data are available for infected children in institutionalized care. We characterized patterns of morbidity and mortality among HIV-1-infected children residing at an orphanage in Nairobi. METHODS: Medical records for 174 children followed over 5 years were reviewed. Mortality was analyzed by Kaplan-Meier methods with adjustment to account for survival in the community before admission. Anthropometric indices were calculated to include mean z scores for weight for length and length for age. Low indices reflected wasting and stunting. Opportunistic infections were documented. RESULTS: Of 174 children, 64 had died. Survival was 70% at age 3 years. Morbidity included recurrent respiratory tract infections, gastroenteritis, parotitis, and lymphoid interstitial pneumonitis. No new cases of tuberculosis disease were noted after admission. Mean z scores for length for age suggested overall stunting (z = -1.65). Wasting was not observed (z = -0.39). CONCLUSION: The optimal form of care for HIV-infected children in resource-poor settings may be the development of similar homes. Absence of tuberculosis disease in long-standing residents may have contributed to improved survival. Stunting in the absence of wasting implied that growth was compromised by opportunistic infections and other cofactors.     

Genetics of reovirus: the relationship of interference to complementation and reassortment of temperature-sensitive mutants at nonpermissive temperature.

Temperature-sensitive mutants of reovirus type 3 are capable of interfering with the replication of wild-type reovirus type 3. The interfering activity correlated with the ability of pairs of mutants to complement at 39°: Pairs of noninterfering mutants (tsD × tsE) yielded efficient complementation (indexes of 10–50); pairs of interfering mutants (including members of groups ts A, B, G) did not produce significant complementation (indexes ～ 1). The ability of pairs of mutants to reassort at 39° generally followed a similar pattern. Thus interference is an important property of ts mutants of reovirus and needs to be considered when genetic interactions are being studied at 39°.     

Allele sharing at six VNTR loci and genetic distances among three ethnically defined human populations

Because of their high degree of polymorphisms, the variable number of tandem repeat (VNTR) loci have become extremely useful in studies involving gene mapping, determination of identity and relatedness of individuals, and evolutionary relationships among populations. However, there are some concerns regarding whether or not the patterns of such genetic variation can be studied by the classical population models that are developed for studying genetic variation at blood groups and protein loci, since VNTR alleles detected by molecular size may not always be identical by descent. Although theoretical and empirical studies demonstrate that this concern is overstated, this study provides further support of the application of the traditional mutation-drift models to predict the pattern of intra- and inter-populational variation at VNTR loci. By comparing genetic variation at six VNTR loci with that at 16 blood groups and protein loci in three ethnically defined populations, we show that the patterns of variability at these two sets of loci are in general parallel to each other. Shared VNTR alleles among populations are generally more frequent than the ones which are not present in every population; the proportion of shared alleles among populations increases with increasing genetic similarity of populations; and the number of VNTR alleles is positively correlated with gene diversity at these loci. All of these observations are in agreement with the prediction of the mutation-drift models, particularly when the possibility of forward-backward mutations are taken into account. This parallelism of genetic variation at VNTR loci and blood groups/protein loci further asserts the potential of using such hypervariable loci for microevoltionary studies, where closely related populations may exhibit considerably less allele frequency differences at the classical blood group and protein loci. © 1992 Wiley-Liss, Inc.     

Verumontanum mucosal gland hyperplasia is associated with atypical adenomatous hyperplasia of the prostate

BACKGROUND: Verumontanum mucosal gland hyperplasia (VMGH) and atypical adenomatous hyperplasia (AAH) are both small glandular proliferations that are histologically and topographically unique. METHODS: One hundred ten randomly selected, whole-mount, radical prostatectomy specimens were reviewed to assess independently the normal histology of the prostatic urethra and periurethral area and the association of AAH with other pathologic features, including VMGH. The degree of nodular hyperplasia was evaluated by total prostate weight for comparison purposes. RESULTS: Atypical adenomatous hyperplasia was found in 37 cases (33.6%) and was nearly always (32/37) associated with nodules of nodular hyperplasia. Verumontanum mucosal gland hyperplasia was present in 32 cases (29.1%; 21 with AAH, 11 without AAH). There was a significant association between presence of VMGH and AAH (P <.001, Fisher exact test). The degree of nodular hyperplasia was not significantly different between prostates with and without VMGH or AAH. CONCLUSIONS: These results suggest that AAH and VMGH occur more commonly in prostates when the other is also present.     

Obesity and upper body fat distribution in Mexican American children from families with a diabetic proband

Upper and centralized body fat distribution is associated with non-insulin dependent diabetes mellitus (NIDDM). Few studies have focused on anthropometric characteristics of preadults from families in which there is a diabetic (NIDDM) proband. This study explores the prevalence of upper and centralized body fatness in Mexican American children from the Diabetes Alert study (1981–1983) in Starr County, Texas. Anthropometric data on 165 males and 224 females 9–19 years include measures of adiposity such as skinfold thicknesses and the body mass index (BMI), a measure of overweight. They show rates of obesity two to three times that of White children of comparable age and sex from National Health Surveys. In comparison with U.S. White subjects, Mexican American adults are shorter, have more adiposity and arm muscle mass and have sitting heights and body breadths at the mean of these dimensions for the U.S. population. Children from Diabetes Alert families show only marginal excess of severe obesity (> 95th percentile of BMI) when compared to the general population of children surveyed in Starr County schools. Girls from these families, but not boys, have excess fatness in the BMI compared to Mexican American children from the Hispanic Health and Nutrition Examination Survey (HHANES); suprailiac skinfold thicknesses are also greater in children of the Diabetes Alert study than in HHANES children. From 1972 through 1982, Mexican American children in South Texas showed an increase in average stature, weight, and the BMI. These data together suggest that excessive obesity exists and may be increasing in children in populations at risk for NIDDM. The prevention of NIDDM in the Mexican American population may be more effective if educational and promotional interventions include the school aged population. © 1993 Wiley-Liss, Inc.     

Cancer mortality in relatives of retinoblastoma patients

The risk of other cancers in relatives of retinoblastoma (RTB) patients was determined by a survey of the mortality experience of siblings, parents, parental siblings, and grandparents of all U.S. or Canadian RTB patients referred to The University of Texas M.D. Anderson Hospital and Tumor Institute between 1944 and 1980. Expected mortality was ascertained by the application of age-, sex-, race-, and calendar year-specific U.S. mortality rates to the observed person-years. Among 607 relatives of 33 unilateral-sporadic RTB probands, no excess in cancer deaths was observed (observed/expected = 18/22). Among 733 relatives of 47 bilateral-familial RTB probands, a slight excess in cancer deaths was observed (41/31). A significant excess in cancer deaths was occurred in relatives under age 55 years (18/9) and in fathers (7/1) of the bilateral RTB probands. To determine whether the cancer excess was related to some unique allele associated with second tumors in RTB survivors, the cancer mortality of 203 relatives of the 14 RTB patients with second tumors was examined, and no excess was observed (11/11). To determine whether the excess might be attributable to an unexpressed RTB gene or precursor, the mortality experience was examined in 6 kindreds in which parents, unaffected by RTB, had more than 1 child with RTB. Among these 72 relatives a significant excess in cancer deaths was observed (8/2). The findings demonstrate a modest overall cancer excess in relatives of hereditary RTB patients and suggest it may be attributable to an unexpressed RTB gene or precursor in a small number of kindreds. Mechanisms for an apparent "precursor" might involve a delayed mutation, genetic mosaicism, or a submicroscopic balanced chromosomal translocation.     

Post-translational modification of proteins by arginine and lysine following crush injury and during regeneration of rat sciatic nerves

Following crush injury to rat sciatic nerves, a crude fraction of the 150,000 g supernatant can post-translationally incorporate [3H]Arg and [3H]Lys into endogenous proteins in amounts approximately 10 times uninjured control nerves. These increases occur in the proximal nerve stump within 2 h of injury and 2 weeks later in a distal segment of nerve containing the tips of the regenerating axons. In the present experiments, the endogenous nerve proteins modified by Arg or Lys in these nerve segments have been identified using two-dimensional polyacrylamide gel electrophoresis. The fraction used to assay for protein modification, the void volume of a Sephacryl S-300 column, was found to contain only a few proteins visible by Coomassie blue staining, one of which is likely to be albumin (68 kDa, pI 6.4). While this protein was modified by both Arg and Lys, the majority of label was found in areas not showing Coomassie blue staining. This indicates that of the many potential targets of post-translational arginylation and lysylation, most are proteins of relatively low abundance. A variety of proteins were modified by Arg or Lys alone while others were modified by both Arg and Lys. A high molecular weight protein (175 kDa, pI 9.0) was modified only by Lys and only at 2 h post crush. Of a variety of modified proteins of approximately 17 kDa one (pI 6.3) was modified by both Arg and Lys and at both time points, while another (pI 9.0) was modified at both time points, but only by Lys. The results show that Arg and Lys can be added post-translationally to a large number of low abundance, soluble sciatic nerve proteins, and that some of those proteins are modified only by Arg or Lys while others are modified by both Arg and Lys. Also, the modification of certain proteins appears to be associated specifically with the immediate response of a nerve to injury (e.g. 88 kDa, pI 7.1) while others are associated with the regenerative period (e.g. 56 kDa, pI 7.4).     

Posttranslational modification of nerve proteins by amino acids

Both axonal and glial components of nerve are capable of carrying out reactions in which Arg, Lys, Leu, Pro, Val, AJa and Ser can be covalently linked to endogenous proteins in reactions which require tRNA but occur in the absence of ribosomes and ribosomal RNA. These posttranslational protein modifications appear to play important roles in nerve regeneration since they are increased more than 10-fold within 2 h of a crush injury in nerves which are capable of regeneration, but are not activated in nerves not capable of regrowth following injury. The regulation of the modification of proteins by Arg and Lys in vivo appears to be the function of separate peptides. The exogenous application of serine protease inhibitors (but not other protease inhibitors) mimics the effect of the endogenous peptides, suggesting that the endogenous regulators have serine protease inhibitory activity. The targets for modification are proteins of low abundance and thus far have been identified only in terms of their molecular weights and isoelectric points. The site of addition of Arg, but not the other amino acids, to target proteins is to the amino terminus. The addition of Arg to an amino terminus is likely to be involved in the ubiquitin mediated proteolysis of the modified protein. One of the most unusual findings in these series of experiments is that in regenerating sciatic nerves, amino acid modified proteins aggregate to form complexes of greater than 2 × 106 Da. The significance of this finding is not known. But we speculate that the aggregate may result from the assembly of an insoluble functional unit of the cell from soluble precursor proteins, and that the trigger for their assembly is amino acid modification.     

A high-yield and simplified procedure for the synthesis of α-[C]Methyl-l-tryptophan

Alpha-[¹¹C]methyl-l-tryptophan (AMT) has been synthesized by stereoselective methylation with [¹¹C]methyl iodide of the lithium-enolate generated by treating dimethyl 2(S),3a(R),8a(S)-(+)-hexahydro-8(phenylsulfonyl) pyrrolo[2,3-b]indole-1,2-dicarboxylate (2) with lithium diisopropyl amide (LDA) at −55 °C, followed by ring opening using trifluoroacetic acid and alkaline hydrolysis of the protecting groups. The crude product was purified by a simple reverse-phase C-18 Sep-Pak procedure. The purified product was isolated with an average radiochemical yield of 53 ± 12% (decay corrected) in 30–35 min from [¹¹C]methyl iodide. At end of synthesis (EOS), 138 ± 35 mCi (n = 24) of product was collected with a specific activity of ca. 1–1.3 Ci/μmol (EOS) (4–5 Ci/μmol @ EOB) starting from 1.5 Ci (EOB) of [¹¹C]CO₂.     

Epitope analysis of the oncofetal antigen alphafetoprotein using monoclonal antibodies.

Alphafetoprotein (AFP), an oncofetal antigen, plays very important roles in the early embryonic life and oncogenesis. Under various physiological and pathological conditions AFP exhibits microheterogeneity, probably as a result of differential expression of its epitopes. To analyse the epitopes we have developed a panel of monoclonal antibodies against human AFP purified by a new and efficient method using an immunoadsorbent consisting of polyclonal antibodies immobilized on cyanogen bromide activated Sepharose. Clones producing antibodies of various isotypes, e.g. IgG1, IgG2a, IgG2b, IgA and IgM have been subcloned and characterized. The antibodies showed high avidity for AFP (with half-maximal binding concentrations between 0.012 and 3.87 nM). Mutual inhibition efficiencies of a panel of 14 monoclonal antibodies were determined by RIA. Based on these inhibition data a computer program was used to group these antibodies with respect to their "epitope specificity distance". As a result of this grouping, clones have been identified which can recognize at least five different epitopes on AFP. This panel of antibodies may be very useful for analysis of the epitopic variation of AFP under various physiological and pathological conditions.