Is subtyping of intestinal metaplasia in the upper gastrointestinal tract a worthwhile exercise? An evaluation of current mucin histochemical stains

Intestinal metaplasia is a premalignant condition that occurs in the upper gastrointestinal tract and can be subdivided into three types (I, II and III). Previous studies suggest that type III carries the highest cancer risk. The high iron diamine/alcian blue (HID/AB) technique traditionally has been used to identify this subtype; however, the technique uses reagents that are toxic and potentially carcinogenic. Therefore, in this study we evaluate various alternative histochemical techniques. Our results indicated that the only suitable alternative is Gomori's aldehyde fuchsin/AB technique. The study also revealed that subtyping of intestinal metaplasia is a subjective procedure, open to varying interpretation. Consequently, we suggest that previous work linking cancer risk to metaplasia subtypes should be viewed with some circumspection.     

Gram-negative bacteria induce proinflammatory cytokine production by monocytes in the absence of lipopolysaccharide (LPS)

Tumour necrosis factor-alpha (TNF-alpha), IL-1alpha and IL-6 production by human monocytes in response to a clinical strain of the Gram-negative encapsulated bacteria Neisseria meningitidis and an isogenic lpxA- strain deficient in LPS was investigated. Wild-type N. meningitidis at concentrations between 105 and 108 organisms/ml and purified LPS induced proinflammatory cytokine production. High levels of these cytokines were also produced in response to the lpxA- strain at 107 and 108 organisms/ml. The specific LPS antagonist bactericidal/permeability-increasing protein (rBPI21) inhibited cytokine production induced by LPS and wild-type bacteria at 105 organisms/ml but not at higher concentrations, and not by LPS-deficient bacteria at any concentration. These data show that proinflammatory cytokine production by monocytes in response to N. meningitidis does not require the presence of LPS. Therapeutic strategies designed to block LPS alone may not therefore be sufficient for interrupting the inflammatory response in severe meningococcal disease.     

Morphological organization and contractile properties of the wrist flexor muscles in the cat

A comparison of the anatomy, fiber type profiles, and contractile properties of the wrist flexor muscles was undertaken in the cat. Isometric contractile characteristics were measured for each muscle. Three muscle fiber types, FG, FOG, and SO, were differentiated by staining cross sections of each muscle for ATPase, NADH diaphorase, SDH, and α-GPD activities. The wrist flexor muscles ranged from less than 1% to 49% SO fiber content; with two of the five heads of the flexor digitorium profundus (FDP) having 1% or less SO fibers (FDP₁—1.07%, FDP₅—0.81%) and the humeral head of the flexor carpi ulnaris muscle (FCU_h) having the greatest content of SO fibers. The mean contraction time (CT) plus one-half relaxation time for an isometric twitch was correlated with the percentage of SO fibers and ranged from 40.5 to 111.8 ms. Except for the FCU (37 ms), the CT was less than 25 ms for the wrist flexor muscles. The uniarticular wrist flexor muscles, the flexor carpi radialis (FCR), and the FCU had the highest percentage of SO fibers and were more fatigue-resistant that the multiarticular muscles. Considerable differences exist in muscle structure, fiber type proportions, and contractile properties between the FCR and FCU, which may be related to functional differences between the two sides of the wrist that may exist during the placement of the foot during locomotion.     

Abnormal intestinal permeability and jejunal morphometry.

The cellobiose and mannitol differential sugar test is a non-invasive investigation of small bowel permeability, in which urinary recoveries of cellobiose and mannitol after a hyperosmolar oral load are expressed as a ratio to give a permeability index. Changes in the cellobiose:mannitol ratio often occur in coeliac disease, but some patients with abnormal permeability have normal jejunums by routine microscopy. Using computed morphometry the perimeter:lamina propria area index of jejunal biopsy samples was measured and compared with the cellobiose:mannitol ratio in three groups of patients: (i) those with coeliac disease with villous atrophy; (ii) those with normal jejunums and sugar test results: and (iii) those with normal jejunums but abnormal sugar test results. In addition to the expected difference in perimeter:lamina propria area index between patients with coeliac disease and those with normal findings (p less than 0.001), the index was also abnormal in patients with normal jejunums but abnormal sugar test results: (p less than 0.001 compared with group 1) and (0.01 greater than p greater than 0.001 compared with group 2). There was a significant overall correlation between the perimeter:lamina propria area index and cellobiose:mannitol ratio (p = 0.001). This study shows that computed jejunal morphometry can identify patients with subtle morphological changes that are related to abnormal intestinal permeability.     

Absorption of amino penicillins from everted rat intestine.

1. Using an in vitro everted gut sac method based on that of Wilson & Wiseman (1954), a number of amino penicillins were tested in order to identify the involvement of any specialized transport mechanisms in their absorption across rat intestine. 2. Only one of the amino penicillins, cyclacillin (1-amino-cyclohexyl penicillin) was shown to be actively transported. The other penicillins appeared to diffuse passively across the intestine. 3. Cyclacillin was found to concentrate against a gradient at 37 degrees C but not at 19 degrees C. 4. Transport of cyclacillin across the mucosal membrane was saturated at mucosal concentrations greater than 1000 microgram/ml. 5. The rate of the forward flux of cyclacillin was many times that of its back flux. 6. No relationship between the active transport of cyclacillin and that of amino acids could be demonstrated.     

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.     

Genetic evidence on the origins of Indian caste populations

The origins and affinities of the approximately 1 billion people living on the subcontinent of India have long been contested. This is owing, in part, to the many different waves of immigrants that have influenced the genetic structure of India. In the most recent of these waves, Indo-European-speaking people from West Eurasia entered India from the Northwest and diffused throughout the subcontinent. They purportedly admixed with or displaced indigenous Dravidic-speaking populations. Subsequently they may have established the Hindu caste system and placed themselves primarily in castes of higher rank. To explore the impact of West Eurasians on contemporary Indian caste populations, we compared mtDNA (400 bp of hypervariable region 1 and 14 restriction site polymorphisms) and Y-chromosome (20 biallelic polymorphisms and 5 short tandem repeats) variation in approximately 265 males from eight castes of different rank to approximately 750 Africans, Asians, Europeans, and other Indians. For maternally inherited mtDNA, each caste is most similar to Asians. However, 20%-30% of Indian mtDNA haplotypes belong to West Eurasian haplogroups, and the frequency of these haplotypes is proportional to caste rank, the highest frequency of West Eurasian haplotypes being found in the upper castes. In contrast, for paternally inherited Y-chromosome variation each caste is more similar to Europeans than to Asians. Moreover, the affinity to Europeans is proportionate to caste rank, the upper castes being most similar to Europeans, particularly East Europeans. These findings are consistent with greater West Eurasian male admixture with castes of higher rank. Nevertheless, the mitochondrial genome and the Y chromosome each represents only a single haploid locus and is more susceptible to large stochastic variation, bottlenecks, and selective sweeps. Thus, to increase the power of our analysis, we assayed 40 independent, biparentally inherited autosomal loci (1 LINE-1 and 39 Alu elements) in all of the caste and continental populations (approximately 600 individuals). Analysis of these data demonstrated that the upper castes have a higher affinity to Europeans than to Asians, and the upper castes are significantly more similar to Europeans than are the lower castes. Collectively, all five datasets show a trend toward upper castes being more similar to Europeans, whereas lower castes are more similar to Asians. We conclude that Indian castes are most likely to be of proto-Asian origin with West Eurasian admixture resulting in rank-related and sex-specific differences in the genetic affinities of castes to Asians and Europeans.     

Activation of normal murine B cells by Echinococcus granulosus.

Echinococcus granulosus protoscolex (PSC) infection of BALB/c mice led, after 4 days, to raised numbers of cells forming plaques with trinitrophenyl-treated sheep red cells and bromelain-treated mouse red cells. The findings were similar in athymic and euthymic CBA mice. Activation of B cells was accompanied by secretion of immunoglobulin, as indicated by the reverse plaque technique. In addition, co-culture of PSC with the 7OZ/3 pre-B-cell led to the induction of differentiation, resulting in the expression of surface immunoglobulin (Ig). It is concluded that E. granulosus is a polyclonal activator of B cells inducing both transformation and differentiation, and that the effect is thymus-independent.     

Mutation of the signal peptide region of the bicistronic gene DSPP affects translocation to the endoplasmic reticulum and results in defective dentine biomineralization

Dentine dysplasia type II is an autosomal dominant disorder in which mineralization of the dentine of the primary teeth is abnormal. On the basis of the phenotypic overlap between, and shared chromosomal location with, dentinogenesis imperfecta type II, a second disorder of dentine mineralization, it has been proposed that the two conditions are allelic. As recent studies have shown that dentinogenesis imperfecta type II results from mutation of the bicistronic dentine sialophosphoprotein gene (DSPP ), we have tested this hypothesis by sequencing DSPP in a family with a history of dentine dysplasia type II. Our results have shown that a missense change, which causes the substitution of a tyrosine for an aspartic acid in the hydrophobic signal peptide domain of the protein, underlies the phenotype in this family. Biochemical analysis has further demonstrated that this mutation causes a failure of translocation of the encoded proteins into the endoplasmic reticulum, and is therefore likely to lead to a loss of function of both dentine sialoprotein and dentine phosphoprotein.