Clinical evaluation of M43: a novel cancer-associated mucin epitope.

A monoclonal antibody to colon carcinoma mucin was found to react with a colon carcinoma-associated carbohydrate epitope. This antibody was used to develop a quantitative solid phase immunoassay, M43. We prospectively and retrospectively evaluated the assay in patients with and without gastrointestinal carcinoma and compared the sensitivity and specificity with that of carcinoembryonic antigen (CEA) and CA 19-9. One hundred ninety-two patients (181 with no evidence of malignancy) referred for upper or lower gastrointestinal endoscopy were prospectively studied. Sera from 172 patients with histologically confirmed gastrointestinal adenocarcinoma were retrospectively studied. Optimal discrimination cutoffs for M43 (5 units/ml), CEA (5 ng/ml), and CA 19-9 (30 units/ml) were determined by receiver operating characteristic curves analysis. M43 was positive in 112 of 151 patients with colorectal carcinoma (sensitivity 74%) and was negative in 167 of 181 patients without carcinoma (specificity 92%). Sensitivity and specificity were 77% and 93% for CEA and 60% and 83% for CA 19-9. Sixty-four % of 73 patients with colorectal carcinoma limited to the bowel wall had a positive M43 with a mean value of 178 units/ml. Eighty-one % of 27 patients with nonhepatic metastasis had a positive M43 with a mean value of 223 units/ml. Eighty-four % of 51 patients with hepatic metastasis had a positive M43 assay with a mean value of 2532 units/ml. Sensitivity in these three groups was 67%, 82%, and 82%, respectively, for CEA and 43%, 68%, and 79%, respectively, for CA 19-9. Of 38 carcinoma patients with a negative CEA, 45% had a positive M43. No correlation between the levels of M43 and CEA in patients with colorectal carcinoma was found. We conclude that M43 is positive in most patients with colorectal carcinoma, even in early stages. As a diagnostic test, its sensitivity and specificity are equivalent to those of CEA. However, the M43 assay is measuring a tumor antigen which is fundamentally different from CEA and which is present in a high percentage of CEA-negative patients.

Treatment of cryptosporidiosis with paromomycin. A report of five cases.

Cryptosporidiosis continues to be one of the most devastating complications of the acquired immunodeficiency syndrome, causing severe, chronic diarrhea that is largely refractory to treatment. More than 60 drugs have been tried in the treatment of cryptosporidiosis, none of which have been consistently successful. We describe the successful treatment of cryptosporidiosis in five patients with acquired immunodeficiency syndrome with oral paromomycin at a dose of 1500 to 2000 mg/d. All five patients had resolution of symptoms and normalization of bowel movements, although one patient later relapsed while receiving paromomycin. Three of five patients cleared Cryptosporidium from the stool. Paromomycin is a promising therapy for cryptosporidiosis in acquired immunodeficiency syndrome and further prospective clinical trials are warranted.

Enteropathic AIDS in Uganda. An endoscopic, histological and microbiological study.

Twenty-three Ugandan patients with enteropathic acquired immunodeficiency syndrome (AIDS, 'slim' disease) were studied. Upper gastrointestinal (GI) endoscopy, colonoscopy, biopsy, stool parasitology and culture were performed. Endoscopy revealed oral and/or oesophageal candidiasis in 22 patients. Stool examination and histology of the upper GI tract showed that 11 patients had cryptosporidiosis and three had isosporiasis (total of 61% of patients with coccidian enteritis). One case of possible Mycobacterium avium mycobacteriosis was also identified. Enteropathic AIDS in Uganda presents with a spectrum of infections similar to that found in developed countries, but the incidence of cryptosporidiosis and isosporiasis is higher.

PIP: Of about 40 patients with presumed enteropathic Acquired Immune Deficiency Syndrome (AIDS), i.e., oral thrush, diarrhea, and weight loss, admitted to Mulago Hospital medical wards, Uganda, from October through November 985, 23 patients were studied with upper gastrointestinal tract endoscopy and stool examination. Those patients chosen for study suffered with diarrhea, weight loss, and oral candidiasis and were willing to tolerate endoscopy. Weight loss was not quantified in most patients, but generally it was profound. 10 of the patients gave a history of genital sores or venereal disease. There were 16 males and 7 females with an age range of 19-47 years. All were sexually active, and all denied homosexuality anal intercourse, and intravenous drug abuse. 4 patients had had blood transfusion. The 23 patients represented a cross-section of the population with most social classes included. 20 patients were seropositive with antibody to HIV. Specimens from 2 patients were lost. 1 patient was seronegative. Apart from 5 patients who had been treated with nystatin for oral thrush and clinically presumed esophageal candidiasis, all the patients had oral thrush at the time of endoscopy. 20 patients had obvious esophageal candidiasis, and 1 patient had the appearance of Kaposi's sarcoma in the esophagus. Stool examination and histology of the upper GI tract showed that 11 patients had cryptosporidiosis and 3 had isosporiasis (total of 61% of patients with coccidian enteritis). 1 case of Mycobacterium avium mycobacteriosis also was identified. The incidence of cryptosporidiosis and isosporiasis is higher in Uganda than in developed countries.

Intolerance of eight ounces of milk in healthy lactose-intolerant teen-agers.

The ability of lactose-intolerant individuals to tolerate 8 ounces of milk was determined in healthy teen-agers. Thirty-two blacks were studied with 50-gm lactose tolerance tests. Nineteen (59%) had a flat blood sugar curve and 13 (39%) also developed bloating, cramps, loose stools, or diarrhea with the test. These latter 13 were defined as lactose-intolerant. Seven of the 13 lactose-intolerant teen-agers (54%) developed abdominal bloating and/or cramps after drinking 8 ounces of milk (half-pint). None had diarrhea. Eight were symptomatic with the equivalent amount of lactose (12 gm) while only one had symptoms with the monosaccharide components of lactose, glucose and galactose. The symptoms with milk and 12 gm of lactose were less severe than with the 50-gm tolerance test. A history of a prior awareness of milk intolerance was obtained from 11 of the 13 lactose-intolerant subjects. At least one half of lactose intolerant teen-agers might be expected to be symptomatic after drinking 8 ounces of milk without other food. Milk intolerance should be considered in the nutritional planning for teen-agers with special attention to members of population groups with a high prevalence of lactose intolerance.

The impact of immigration on the increasing incidence of hepatocellular carcinoma in the United States.

AIMS: To assess if the rising incidence of hepatocellular carcinoma in the United States can be accounted for by immigration and an ageing population, or is a true increase among the USA-born residents. METHODS: Design--A retrospective chart review. Setting--Urban, multiethnic hospital and specialty clinics in a large indigent health system in Houston, Texas. Subjects--Approximately 23,000 admissions and 143,000 out-patient clinic visits each year from 1992 through 2001 were assessed. A total of 494 patient records were selected and reviewed because of suspicion of hepatocellular carcinoma. Analysis- Hepatocellular carcinoma was confirmed by histopathology, alpha-fetoprotein level >400 ng/mL, and suggestive imaging studies. The age-adjusted incidence was determined and causative factors were identified. RESULTS: About 111 cases of confirmed hepatocellular carcinoma were found. The age-adjusted incidence rose from 3.44 per 100,000 hospital admissions during 1992-1996 (95% confidence interval: 2.86-4.02) to 5.19 during 1997-2001 (95% confidence interval: 4.41-5.97). The proportion of patients of non-USA place of birth decreased between 1992-1996 and 1997-2001 (46-24%, respectively, P = 0.03). Fifty-two per cent and 68% were hepatitis C virus-positive respectively; 37% and 34% were hepatitis B surface antigen-positive respectively; 46% and 59% had a history of alcohol abuse; and 22% and 11% had no identifiable risk factors. CONCLUSIONS: The incidence of hepatocellular carcinoma within the greater Houston area has increased during the past decade, rising by 51% from 1992-1996 to 1997-2001. This increase is not from immigration or population ageing but represents a true rise among the native born population. Hepatitis C and alcoholic cirrhosis are associated with a majority of cases, particularly in the latter half of the decade.

Randomized controlled trial of clarithromycin and ethambutol in the treatment of Crohn's disease.

BACKGROUND: A mycobacterial infection may be the cause of Crohn's disease in some patients. Measurement of intestinal permeability may identify Crohn's disease patients with a high likelihood of relapse and may quantify the severity of intestinal injury. AIM: To assess the effect of 3 months of clarithromycin and ethambutol on the disease activity and intestinal permeability in patients with Crohn's disease at high risk of relapse. METHODS: Patients with Crohn's disease, with a lactulose-mannitol permeability test above 0.03, were randomly assigned to receive either clarithromycin, 500 mg twice daily, and ethambutol, 15 mg/kg daily, or identically appearing placebo for 3 months in addition to their regular therapy. The Harvey-Bradshaw index and the lactulose-mannitol test were assessed in a blind fashion every 3 months for 12 months. RESULTS: Thirty-one patients were randomized to receive either drugs (n=15) or placebo (n=16). The groups were similar in age, sex, duration of disease, location of disease, past complications and disease severity. Specifically, there was no difference between the drug or placebo groups in the mean Harvey-Bradshaw index (4.8 vs. 4.4), number with active disease (33% vs. 44%) and mean lactulose-mannitol test (0.06 vs. 0.10). During the 12-month follow-up period, there were no consistent, statistically significant differences in the mean Harvey-Bradshaw index or lactulose-mannitol test between treatment and placebo groups. Individual patients showed either improvement or worsening of these indices, but these were not related to study medication. Specifically, no 'cures' were noted with anti-mycobacterial treatment. CONCLUSIONS: Three months of treatment with clarithromycin and ethambutol does not benefit Crohn's disease patients who are receiving standard medical therapy.

Tuberculous lymphadenitis associated with human immunodeficiency virus (HIV) in Uganda.

Sixteen adults presented with lymphadenopathy which was tuberculous on biopsy; they were all seropositive for human immunodeficiency virus (HIV-1), but none had the clinical criteria of the acquired immunodeficiency syndrome (AIDS). The biopsy specimen showed caseating tuberculosis, with scanty or no visible acid fast bacilli in seven cases; the remaining nine had a poor cellular reactivity with numerous bacilli. Antituberculous chemotherapy for two months reduced the lymphadenopathy. Two patients subsequently developed AIDS. Mycobacterial cultures were not performed, but the infection was almost certainly Mycobacterium tuberculosis. The space-time clustering of tuberculous lymphadenitis now seen in Kampala, and the unusual non-reactive histopathology, are typical of the impairment of cellular immunity induced by HIV infection.

PIP: Tuberculosis is not among the infections currently included in the clinical case description of AIDS. However, tuberculous lymphadenitis is emerging as an increasingly common concomitant infection associated with HIV-1 seropositivity in Africa. 16 HIV-positive patients presenting at Mulago Hospital, Kampala, in 1986, with lymphadenopathy were studied. Lymph node biopsies were done on all 16, but only 7 of the histopathologic specimens showed a normal immune response to tubercle bacilli. The remaining 9 showed numerous bacilli but absent or weak cellular immune response. All patients responded to standard antituberculosis drug therapy; 2 patients developed clinical AIDS. Since HIV seropositivity seems to predispose to nontypical tuberculosis, it is recommended that in future cultures be done on tuberculous tissues from HIV-positive patients in Africa.

Lack of association of hepatosplenic schistosomiasis and alpha-1-antitrypsin deficiency.

To evaluate the role of alpha-1-antitrypsin deficiency in the pathogenesis of hepatosplenic schistosomiasis, alpha-1-antitrypsin was measured in 90 patients with schistosomal splenomegaly and in 87 phenotyping was also done. All levels were in the normal range except for those of two patients who were shown to have the heterozygous deficiency state, PiMZ. The phenotypes found in the 87 were as would be expected in a normal population. Alpha-1-antitrypsin deficiency does not play a significant role in the pathogenesis of hepatosplenic schistosomiasis.

Immune responses during human schistosomiasis mansoni. VII. Further analysis of the interactions between patient sera and lymphocytes during in vitro blastogenesis to schistosome antigen preparations.

The lymphocyte blastogenic responses of chronic schistosomiasis mansoni patients were tested in vitro in medium supplemented with either normal human serum or patients' serum (either autologous or third party). As expected, when patients' lymphocytes were cultured in patient sera, many of them (75--78%) displayed reduced responsiveness to schistosome antigens (derived from either the cercariae, adult worms or eggs of Schistosoma mansoni), but not to Candida albicans extract. For decreased blastogenesis to be manifest, a combination of both suppressive sera and suppressible cells was required; however, some patients had nonsuppressible cells and not all sera were suppressive. In an attempt at classification, four categories of patient responsiveness concerning serosuppression are proposed. The categories depend on the suppressive capabilities of patient sera and the response of patient lymphocytes to suppressive sera. By individually testing the capabilities of each patient's lymphocytes and sera in relationship to each antigenic preparation, we were able to assign the majority of patient responses to a given category. It is hoped that by using these categories, a better understanding of the mechanisms concerning serosuppression will be obtained.

Humoral immune responses in human hepatosplenic schistosomiasis mansoni.

The development of hepatosplenic schistosomiasis in humans cannot always be related to the intensity of infection. A study was designed to identify different humoral immunologic responses to Schistosoma mansoni in patients with and without hepatosplenic disease. Twenty-four patients with active hepatosplenic disease were closely matched for age, sex, and fecal egg counts with twenty-four patients with only intestinal disease. A serum sample from each of these patients was tested for antibodies to the major soluble egg antigen (MSA1) by radioimmunoassay, for total and IgM antibodies to egg and worm antigenic preparations by ELISA, and for its ability to suppress antigen stimulated lymphocyte blastogenesis. No difference was found using these assays between the hepatosplenic and the intestinal schistosomiasis patients.

Application of the enzyme linked immunosorbent assay (ELISA) for the serodiagnosis of Schistosoma mansoni infections in St. Lucia.

As part of our search for a serodiagnostic assay to replace the expensive and tedious stool examination in the diagnosis of Schistosoma mansoni infection, we have studied the sensitivity, specificity and quantitative features of an enzyme linked immunoassay (ELISA) using crude S. mansoni egg antigen preparation. Results of studies carried out in both London and St. Lucia indicate that the assay can give useful serodiagnostic information ranging from 82 to 99.5% sensitivity, depending on level of infection intensity and method of blood collection and 100% specificity in St. Lucian/St. Vincent populations. The St. Lucia study also showed that the assay could be operated in a qualitative form in an endemic area.

Comparison of ELISA, radioimmunoassay and stool examination for Schistosoma mansoni infection.

A comparison was made of the sensitivity and specificity of four diagnostic tests for Schistosoma mansoni infection in a community of 516 untreated persons in St. Lucia, West Indies. Prevalence of infection as obtained by: (i) the Bell filtration technique was 44.4% (one filter) and 63.2% (three filters); (ii) the Kato thick smear, 60.2%; (iii) by radioimmunoassay (RIA), 73.3%; and (iv) enzyme-immunoassay (ELISA) 70.9%. The age distribution of persons serologically positive but parasitologically negative showed these to be mostly children and persons 40 years old and over. By means of a statistical test due to Cochrane, it was concluded that there was no evidence to indicate a difference between paired serological tests and paired parasitological tests in their diagnostic capability. There was a very significant difference between the Bell technique and the other three tests. The ELISA emerged as a less satisfactory test than the RIA or the Kato thick smear. The levels of sensitivity and specificity of each test were measured by Armitage's "J" index. The reliability of the Bell filtration technique was 64%, of the ELISA 68%, of the RIA 78% and of the Kato 85%.

Infectious esophagitis.

This article presents the epidemiology, pathogenesis and pathology, clinical manifestations, and diagnosis and treatment of Candida, herpes simplex virus, cytomegalovirus, Mycobacterium tuberculosis, Aspergillus, histoplasmosis, blastomycosis, and HIV. Uncommon AIDS-related esophageal infections are also discussed.

Understanding intestinal spore-forming protozoa: cryptosporidia, microsporidia, isospora, and cyclospora.

OBJECTIVES: To summarize recent information about the "new" gastrointestinal protozoal pathogens (cryptosporidia, microsporidia, isospora, and cyclospora) and to help practicing clinicians integrate this information into their clinical databases by emphasizing the similarities among these organisms. DATA SOURCES: Relevant English-language articles published between 1988 and 1995 were identified through a MEDLINE search done using the names of the intestinal spore-forming protozoa. Articles cited in the bibliographies of these and other articles were searched manually. STUDY SELECTION: Studies that contained information on the history, taxonomy, life cycle, epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of the pathogens were reviewed. DATA EXTRACTION: Cryptosporidium parvum, Isospora belli, Cyclospora cayetanensis, Enterocytozoon bieneusi, and Septata intestinalis are intestinal spore-forming protozoa that cause intracellular infections, predominantly in the epithelial cells of the intestine. They are transmitted either by stool from person to person or through contaminated water or food by an infectious particle called a spore or oocyst. Asymptomatic infections occur; the most common symptom of infection is diarrhea. Infections have been associated with intestinal inflammation, disordered architecture (such as villus blunting), and abnormal function (for example, malabsorption). Mild to moderate, self-limited diarrhea is common in healthy persons, but patients with immune dysfunction can have severe intestinal injury and prolonged diarrhea. Diagnosis is made by a microscopic examination of the stool and the use of appropriate staining techniques. Effective antibiotic treatment for prolonged infection in immunocompromised patients is available for most of these infections. CONCLUSIONS: The intestinal spore-forming protozoa are four frequently identified gastrointestinal pathogens that have important similarities in epidemiology, disease pathogenesis, clinical manifestations, diagnosis, and treatment.

Gastrointestinal cytomegalovirus disease.

OBJECTIVE: To describe the pathogenesis of gastrointestinal cytomegalovirus (CMV) disease, the types and locations of gastrointestinal lesions, the clinical settings in which they occur, and the specific methods available to diagnose and treat the disease. DATA SOURCES: Relevant English-language articles were identified through a MEDLINE search from 1985 to 1992. Articles referenced in the bibliographies of these articles and others were searched by hand. STUDY SELECTION: All articles that documented the occurrence of gastrointestinal CMV infection in humans, based on the finding of typical cytomegalic cells in histologic specimens, were selected for review. DATA EXTRACTION: Studies were grouped by content pertaining to pathogenesis, clinical setting, gastrointestinal location, diagnosis, or treatment. DATA SYNTHESIS: Gastrointestinal CMV disease is an erosive or ulcerative process that can occur at any location in the gastrointestinal tract, from mouth to rectum. Cytomegalovirus infection of columnar epithelial cells, endothelial cells, myocytes, and fibroblasts causes tissue destruction and ulceration. Serious CMV disease most frequently occurs with immune deficiency, such as the acquired immunodeficiency syndrome, after organ transplantation, after cancer chemotherapy, and after steroid therapy. Symptoms and signs depend on which part of the gastrointestinal tract is involved. Diagnosis depends on a positive mucosal biopsy that shows the presence of CMV by histopathologic or other techniques. In patients with persistent immune deficiency, progressive intestinal disease and death are frequent. Treatment with ganciclovir or foscarnet often heals intestinal lesions. CONCLUSIONS: Internists should be aware of the various clinical settings and locations in the gastrointestinal tract in which CMV disease occurs. Patients with immune deficiency and gastrointestinal signs and symptoms should have imaging tests and mucosal biopsies to investigate the possibility of CMV intestinal disease. Treatment with antiviral chemotherapy improves outcome in many patients.

Viral infections of the gastrointestinal tract.

Acute gastroenteritis is common in adults. It can occur in institutional epidemics or epidemics of food-borne illness; in these cases, caliciviruses are the major cause of the condition. When acute gastroenteritis occurs in nonepidemic form, its causes are less clear. It may be due to caliciviruses or to the less common serotypes of childhood gastroenteritis viruses, such as rotavirus, astrovirus, and adenovirus. The pathogenesis of acute viral gastroenteritis is not completely understood. Old evidence suggests that mild villus damage is responsible, but new evidence indicates that active secretion and motility disturbance may be involved in the production of symptoms. Five common viruses can remain latent in gastrointestinal tissues and produce disease many years after initial infection. Two major herpesviruses, cytomegalovirus and herpes simplex virus, cause ulcerative disease of the gastrointestinal tract. This disease occurs in healthy persons but is more common and more severe in immunocompromised patients. Three other viruses--Epstein-Barr virus, human papilloma virus, and human herpesvirus-8--are implicated in benign and malignant proliferative diseases of the gastrointestinal tract. Epstein-Barr virus has been associated with immunoproliferative disease after transplantation and may also cause small-bowel and colonic lymphoma in healthy adults. It causes most AIDS-related lymphomas. Human papillomaviruses cause anorectal condyloma and anal cancer. Human herpesvirus-8 causes gastrointestinal Kaposi sarcoma.

AIDS in Uganda--clinical and social features.

PIP: This article highlights the clinical and social features of the AIDS epidemic in Uganda. AIDS is already the most common cause of admission and death among hospitalized adults in many parts of the country. 1 million adults out of a country of 17 million people are estimated to be HIV-seropositive. With such a large population of HIV infected people high risks no longer exist and knowing a patient's social history rarely helps in diagnosing AIDS. Tuberculosis is now ubiquitous with a doubling in the number of cases from 1984 to 1987. With few reliable laboratory resources, a patient with AIDS with a pulmonary infiltrate can present a dilemma to a Ugandan health worker. Even though HIV testing is not routinely available in Uganda where resources are being used to repair a damaged economy, the clinical criteria for diagnosing AIDS may actually be more than 92% specific. A benefit to the clinical diagnosis is that many treatable non-HIV-related illnesses, such as diabetes, are frequently undiagnosed as AIDS related syndrome in people who are shown to be HIV seropositive by routine testing. Since AIDS immunosuppresses patients, the local opportunistic infections indicate the common environmental pathogens. In Uganda the highly prevalent infections are: syphilis, 5-30%; cytomegalovirus infection, 100%; toxoplasmosis, 50-75%; and chronic hepatitis B antigenemia, 15%. Unfortunately, there is little a Ugandan physician can do for AIDS patients with limited health resources. Counseling is controversial due to expected social norms and arguments about the situation's futility. A huge infusion of education, money, and personnel will be needed to combat AIDS in Uganda.^ieng