Prenatal risk factors of wheezing at the age of four years in Tanzania.

BACKGROUND: A study was undertaken to assess the interactions between prenatal exposures, early life infections, atopic predisposition, and allergen exposures in the development of wheezing up to the age of 4 years in a tropical region of Africa. METHODS: The study subjects comprised children born at the district hospital in Ifakara, Tanzania during a 1 year period who were participating in a trial of iron supplementation and malaria chemoprophylaxis during the first year of life and followed for up to 4 years. From this group of subjects, 658 (79%) participated in the interview at 18 months and 528 (64%) in a second interview at 4 years. Wheezing was measured with the ISAAC questionnaire. A hospital based inpatient and outpatient surveillance system was set up to document all attendance by study children for any cause, including episodes of clinical malaria and lower respiratory tract infections. Total IgE levels and malaria parasites were measured in maternal and cord blood. Total IgE was also measured at 18 months of age. Indoor environmental levels of Der p I and Fel d I were determined using an enzyme linked immunosorbent assay at the same time as the interview at the age of 18 months. RESULTS: The prevalence of wheezing at 4 years is common in Ifakara (14%, range 13-15%). The presence of malaria parasites in cord blood (odds ratio, OR = 6.84, 95% CI 1.84 to 24.0) and maternal asthma (OR = 8.47, 95% CI 2.72 to 26.2) were positively associated with wheezing at the age of 4 years, and cord blood total IgE was negatively associated (OR = 0.24, 95% CI 0.07 to 0.85) (all p<0.05). Parasitaemia at birth was not related to total IgE levels in cord blood (p=0.6). Clinical episodes of malaria during infancy were not associated with wheezing, and nor were levels of indoor aeroallergens. CONCLUSION: These findings suggest that events occurring during pregnancy may play a role in the future appearance of wheezing, although the results must be interpreted with caution because of the small numbers studied.

Placental malaria is associated with cell-mediated inflammatory responses with selective absence of natural killer cells.

Immunosuppression, particularly of cell-mediated responses, has classically been thought to play a major role in the increased susceptibility to malaria observed in pregnant women. An immunohistochemical characterization of the inflammatory infiltrate in a group of 41 placentas from women living in a Plasmodium falciparum-hyperendemic area in Tanzania revealed a marked increase in the number of monocytes and macrophages and cytotoxic T cells in the intervillous space of placentas with active malaria infection, compared with noninfected placentas, placentas from women with past infection, and a control group of placentas from Spain. This increase was associated with the severity of the infection. High numbers of monocytes and macrophages were associated with low birth weight. We also detected a complete absence of NK cells in the intervillous space in all placentas. This apparently physiological absence of NK cells may contribute to hindering the clearance of the parasite. These results indicate that placental malaria does not appear to be associated with cell-mediated immunosuppression. The role of the absence of NK cells in increased susceptibility to malaria needs to be further elucidated.

A prognostic model for predicting survival in cirrhosis with ascites.

BACKGROUND/AIMS: Parameters evaluating renal function and systemic hemodynamics are of prognostic significance in cirrhosis with ascites but are rarely used in the evaluation of survival of these patients. The aim of the current study was to develop a prognostic model to estimate survival of patients with cirrhosis and ascites. METHODS: 216 Cirrhotic patients admitted to hospital for the treatment of ascites were evaluated. Thirty-two demographic, clinical and laboratory variables, including parameters assessing liver and renal function and systemic hemodynamics, were analyzed as predictive factors of survival by using a Cox regression model. RESULTS: Four variables had independent prognostic value: renal water excretion, as assessed by measuring diuresis after water load, mean arterial pressure, Child-Pugh class, and serum creatinine. According to these features a prognostic index was calculated that allows to estimate survival in patients with cirrhosis and ascites. The model accurately predicted survival in an independent series of 84 patients with cirrhosis and ascites. CONCLUSION: A prognostic model that uses four easily available variables and predicts prognosis in cirrhotic patients with ascites has been developed. This model may be useful in the evaluation of patients with ascites for liver transplantation.

Intranasal challenge with aspirin in the diagnosis of aspirin intolerant asthma: evaluation of nasal response by acoustic rhinometry.

BACKGROUND: Nasal provocation tests with lysine-aspirin have recently been introduced for assessment of aspirin intolerant asthma. A study was undertaken to evaluate the usefulness of acoustic rhinometry, a new non-invasive technique, in the diagnosis of aspirin intolerant asthma/rhinitis. METHODS: Fifteen patients with aspirin intolerant asthma/rhinitis (nine women, mean (SD) age 54.7 (14) years), eight patients with aspirin tolerant asthma/rhinitis (three women, mean (SD) age 52.6 (7.8) years), and eight healthy subjects (two women, mean (SD) age 32.5 (9.7) years) were studied. All subjects were challenged with saline (0.9% NaCl) and 25 mg lysine acetylsalicylic acid (L-ASA) instilled into each nostril of the nose on two separate days. The clinical response was evaluated based on nasal symptoms (sneezes, itching, secretion and blockage). The nasal response was measured by acoustic rhinometry. Symptoms and rhinometry curves were recorded at 10 minute intervals for three hours, one hour before challenge and two hours after challenge. RESULTS: L-ASA challenge induced a significant increase in symptoms in patients with aspirin intolerant asthma/rhinitis. No differences in the clinical response were detected in those with aspirin tolerant asthma/rhinitis or healthy subjects. L-ASA challenge induced a significant decrease in nasal volume measured by acoustic rhinometry in aspirin intolerant patients. No differences were detected between the challenges in aspirin tolerant patients. If a 25% decrease in nasal volume is taken as the cut off point, the specificity of the test was 94% and the sensitivity reached 73%. The nasal challenge was well tolerated by all subjects. CONCLUSION: Acoustic rhinometry may be used to study the nasal response to L-ASA. Nasal challenge with L-ASA is safe and can be used as a diagnostic test even in asthmatic patients with severe bronchial obstruction.

Large deletions of chromosome 9p in cutaneous malignant melanoma identify patients with a high risk of developing metastases. Hospital Clinic Malignant Melanoma Group, University of Barcelona.

Cutaneous malignant melanoma (CMM) is an aggressive tumour with a high metastatic potential. Deletions of chromosome 9p have been detected in CMM, some of which involve the CDKN2A/p14ARF genes. Loss of heterozygosity (LOH) of 16 microsatellite markers on 9p and mutations in the CDKN2A/p14ARF genes had been previously studied in 32 melanoma patients by our group. 9p deletions were detected in 15 primary tumours (45.5%) and are here correlated with the clinical outcome over 5 years and compared with classical prognostic factors. Eight of the 32 patients developed metastases (25%). The metastases were all detected within 768 days of the initial diagnosis. The patients without metastases were last monitored at least 1621 days after diagnosis. None of the 21 patients with more than eight microsatellites conserved developed metastases, whereas all of the eight patients who developed metastases had eight or more markers deleted. The sensitivity of this analysis to predict metastases was 100% (specificity 84%), whereas the sensitivity for the same sample using a Breslow thickness > 3 mm was 62.5% (specificity 68%). LOH of eight or more of the 9p microsatellite markers is therefore a useful prognostic factor to predict the development of metastases in the first 4.4-6.3 years (1621-2294 days).

p53 expression predicts progression and poor survival in T1 bladder tumours.

OBJECTIVES: Histological grade (G) is the only parameter proved to have prognostic value for progression in T1 transitional cell carcinoma (TCC) of the bladder, although it is considered inaccurate to make clinical decisions on individuals. The aim of the present study was to evaluate the prognostic relevance of p53 expression in T1 TCC of the bladder. METHODS: Clinical records of 207 patients with T1 TCC of the bladder were reviewed for clinical parameters reported to influence the evolution of superficial bladder cancer. Among these 207 patients, 40 developed muscle-invasive disease (20 G2 and 20 G3). A retrospective case-control study was then carried out comparing the latter 40 tumours with 40 control tumours matched by grade, sex, age, number and size of the tumours, chemical exposure and presence of carcinoma in situ. p53 immunostaining with monoclonal antibody was performed in these two groups. RESULTS: Histological grade was the only clinical parameter that influenced evolution. p53 expression correlated with tumour progression, since it was observed in 21 out of 24 p53-positive tumours and in only 20 of 56 p53-negative tumours (p<0.0001), showing a specificity of 93. 5% and a sensitivity of 53%. p53 expression correlated as well with patient survival, being 39% in patients with p53-positive tumours and 80% in patients with p53-negative tumours at 60 months (p<0. 0001). CONCLUSIONS: p53 protein expression has prognostic value for survival and progression in T1 bladder tumours and can be used for early detection of poor-prognosis T1 bladder tumours.

The impact of placental malaria on gestational age and birth weight.

Maternal malaria is associated with reduced birth weight, which is thought to be effected through placental insufficiency, which leads to intrauterine growth retardation (IUGR). The impact of malaria on preterm delivery is unclear. The effects of placental malaria-related changes on birth weight and gestational age were studied in 1177 mothers (and their newborns) from Tanzania. Evidence of malaria infection was found in 75.5% of placental samples. Only massive mononuclear intervillous inflammatory infiltration (MMI) was associated with increased risk of low birth weight (odds ratio ¿OR, 4.0). Maternal parasitized red blood cells and perivillous fibrin deposition both were associated independently with increased risk of premature delivery (OR, 3.2; OR, 2.1, respectively). MMI is an important mechanism in the pathogenesis of IUGR in malaria-infected placentas. This study also shows that placental malaria causes prematurity even in high-transmission areas. The impact of maternal malaria on infant mortality may be greater than was thought previously.

[The progression of hepatic fibrosis in chronic hepatitis C]. / Progresión de la fibrosis hepática en la hepatitis C crónica.

UNLABELLED: The natural history of liver fibrosis in 47 untreated patients with chronic hepatitis C and no cirrhosis, as well as the factors associated with its progression, were evaluated by examining two consecutive liver biopsies, separated by an average interval of 64.8 +/- 62.9 months (12-244). In all the biopsies, the degree of necroinflammation and the stage of fibrosis were determined on a scale from 0+ to 4+. In 53% of the patients, liver fibrosis did not progress. The interval between biopsies was significantly higher in those who progressed from one stage to another (85 +/- 77 months) than in those who did not (41 +/- 27 months), p = 0.014. Two factors were independently associated with a greater risk of fibrosis progression: a history of daily alcohol intake > or = 80 g (p = 0.02) and having acquired an infection through a known parenteral mechanism such as blood transfusion, major surgery or hemodialysis (p = 0.018). Necroinflammation was significantly diminished in the second biopsy due to a lesser necrosis and inflammation of the lobules. IN CONCLUSION: a) liver fibrosis progression is independent of necroinflammation; b) progression is related to the duration of the disease and with the mechanism of transmission, and c) it is aggravated by excessive alcohol consumption.

Placental pathology in malaria: a histological, immunohistochemical, and quantitative study.

To characterize the histological changes in malarial placentas and their relationship with parity and maternal and cord parasitemias, we conducted a histological study on 1,179 placentas from Ifakara, Tanzania, an area with intense and perennial malaria transmission. Immunohistochemical and quantitative studies for CD45, fibrin, and villous area were performed in 60 cases. Four hundred fifteen placentas (35.2%) showed parasites (active infections); in 303 of them, parasites co-existed with pigment covered by fibrin (chronic infections), and in 112 only parasites were detected (acute infections). Four hundred seventy-five cases (40.3%) showed hemozoin deposition without parasites (past infections). Of women with parasitized placentas, 46.3% did not show parasites in the peripheral blood. Basal membrane thickening (P = .002), fibrinoid necrosis (P = .004), and prominence of syncytial knots (P = .031) were associated with active malarial infection. No quantitative differences for perivillous fibrin deposition or villous area were found. The most significant association with active malarial infection was intervillous infiltration by mononuclear inflammatory cells (P < .001). Chronic infections were associated with the most severe changes, particularly intervillous mononuclear inflammation (OR, 28.7; 95% CI = 16.0 to 51.5, P< .001). Past infections showed only minimal differences with noninfected placentas. Primiparas showed chronic infections more frequently than multiparas (52% v 15%, P < .001). They also showed significantly higher placental parasitemias and intervillous inflammatory infiltrate. In conclusion, placental histology is more sensitive than peripheral blood examination in detecting malarial infection during pregnancy. Most malarial infections recover during pregnancy, leaving few residual changes in the placenta. Intervillous inflammation is the most frequent finding associated with malaria and is especially severe in primiparas, suggesting that mechanisms other than immunosuppression are responsible for the high susceptibility in this group.

Clinical evaluation of an in-house IS6110 polymerase chain reaction for diagnosis of tuberculosis.

The aim of this study was to clinically validate a heminested polymerase chain reaction (PCR) method, based on the IS6110 insertion segment of Mycobacterium tuberculosis complex, for the diagnosis of tuberculosis. Samples of pulmonary, extrapulmonary and blood origin were collected prospectively from 331 patients. All samples were processed to detect acid-fast bacilli by direct stain, culture and PCR. The gold standard comparison was a clinically based final case definition of tuberculosis corresponding to group 3 of the American Thoracic Society's classification system. The sensitivities of stain, culture and PCR were 41%, 65% and 59%, respectively. Overall specificity exceeded 97% for all techniques. The combination of PCR and direct stain achieved a sensitivity similar to that of culture alone. The PCR method detected 74 of 95 (78%) culture-positive results. In a hospital setting, PCR could be a useful, reliable tool for diagnosis of tuberculosis and may be introduced as a complementary routine diagnostic laboratory method.

Urinary porphyrin excretion measurements in healthy neonates.

The objective of this study was to establish normal reference ranges for porphyrins in healthy neonates. There is little information about urinary porphyrin excretion in this age group. This knowledge may provide an early diagnostic tool for detecting subtle alterations or latent forms in disorders of heme biosynthesis. Fifty healthy neonates were selected from the Department of Obstetrics. Total urinary porphyrins in random specimens were analysed by a spectrofluorometry method. The measurement of porphyrin fractions was made by fluorometric high-performance liquid chromatography (HPLC). The results were adjusted to urinary creatinine excretion to correct any imprecision and interindividual variation in body mass. The urinary total porphyrin had a median value of 331.50 (nmol/L). A statistically significant relationship between total porphyrin (nmol/L) and creatinine (mmol/L) was found (p < 0.01). The porphyrin/creatinine ratio showed a median value of 56.30 nmol/mmol creatinine. The study of individual porphyrins revealed that coproporphyrin and uroporphyrin were the major porphyrins excreted in neonates (coproporphyrin represents 81.98% and uroporphyrin 16.64% of total porphyrin); in both cases, isomer I was predominant with median values of 22.36 and 6.25 nmol/mmol creatinine, respectively. No significant relationships were found between porphyrin excretion and sex, gestational age, weight, or height. Our data provide the reference limits for porphyrins in neonates as a diagnostic guideline for evaluation of subtle alterations in heme biosynthesis.

Prognostic significance of hepatic encephalopathy in patients with cirrhosis.

BACKGROUND: There are numerous studies concerning the natural history and prognostic factors in cirrhosis, the results of which are useful in selecting liver transplant candidates. However, little attention has been paid to the prognostic significance of hepatic encephalopathy despite the high frequency of this complication. METHODS: We reviewed the charts of 111 cirrhotic patients who developed a first episode of acute hepatic encephalopathy to determine their survival probability and to identify prognostic factors. RESULTS: During follow-up (12+/-17 months), 82 (74%) patients died. The survival probability was 42% at 1 year of follow-up and 23% at 3 years. With univariate analyses followed by a multivariate analysis, 7 out of 30 clinical and standard laboratory variables were significantly associated with poor prognosis: male sex, increased serum bilirubin, alkaline phosphatase, potassium and blood urea nitrogen, and decreased serum albumin and prothrombin activity. Patients were classified into two groups according to a prognostic index calculated from these 7 variables. Survival probability at 1 and 3 years was 73% and 38%, respectively, in patients with a low prognostic index, and 10% and 3% in patients with a high prognostic index. CONCLUSION: Hepatic encephalopathy is associated with short survival in cirrhotic patients. Although these patients can be classified into several groups with a different prognosis, the survival probability in every group is lower than that currently expected after liver transplantation. Therefore, cirrhotic patients developing a first episode of acute hepatic encephalopathy should be considered as potential candidates for this therapeutic procedure.

Effects of a startling acoustic stimulus on reaction time in different parkinsonian syndromes.

BACKGROUND: The functional assessment of the startle circuit is usually done by analyzing the acoustic startle response (ASR). However, a startling acoustic stimulus (SAS) also induces changes in the excitability of neural structures that can be demonstrated by studying the SAS-induced change in the behavior of certain neurophysiologic responses. OBJECTIVE: To examine the effects induced by an SAS on voluntary reaction time in patients with parkinsonian syndromes (StartReact effect) and to compare the results with those obtained in a group of age-matched healthy volunteers. METHODS: Twelve patients with idiopathic PD (IPD), seven patients with progressive supranuclear palsy (PSP), seven patients with multisystem atrophy (MSA), and seven healthy age-matched control volunteers performed a simple visual reaction time task and received SAS together with the "go" signal in random trials. RESULTS: Baseline reaction time was significantly slower in PSP patients than in control subjects and MSA patients. The SAS induced a significant shortening of the reaction time in control subjects and in patients with IPD and MSA, but not in patients with PSP. The percentage of reaction time shortening with regard to the baseline values also differed significantly between PSP patients and the other groups of subjects. The StartReact effect was consistent throughout the experiment and showed reduced habituation with repeated testing. CONCLUSIONS: The results are consistent with an abnormal function of the startle circuit in patients with PSP and agree with previous studies using the ASR. The reduced habituation of the StartReact effect favors its clinical applicability in the assessment of differences between patients with parkinsonian syndromes.

Massive chronic intervillositis of the placenta associated with malaria infection.

Massive chronic intervillositis (MCI) is an infrequently recognized placental lesion thought to be of immunologic origin that has been associated with poor fetal outcome. It is characterized by a prominent inflammatory infiltrate in the intervillous space, composed mainly of monocytes and macrophages that can simulate a maternal malignant disorder involving the placenta. The villi are characteristically spared. We report 74 cases of placental malarial infection with morphologic features of MCI. In all cases, the massive inflammatory infiltrate was limited to the intervillous space, which appeared largely obliterated. Increased fibrin deposition and prominent syncytial knots were frequent associated findings. Inflammatory cells were CD45 and CD68 positive, consistent with a monocyte-macrophage population. Some polymorphonuclear leukocytes and scattered T and B lymphocytes were also present. Villi were not inflamed. Malarial pigment was present in all cases, and parasitized maternal erythrocytes were evident in 73 of 74 patients. The histologic pattern of MCI was observed in 17.6% of placentas with malarial parasites. Malarial MCI affected predominantly primigravida women (77%) and was associated with a reduced birth weight, which in 39 (53%) of the infants was less than 2500 g, and a low gestational age. None of the infants with placentas with MCI died in the early neonatal period. Morphologic changes of MCI are seen in a significant percentage of placentas with malarial infection, especially in primigravida women, and are associated with a low birth weight. Malarial infection should therefore be considered in the differential diagnosis of massive intervillous infiltrates.