Symptom-free Stage Research Articles

The Control of Apoptotic Death in the Cells of Granulomatous Inflammatory Lesions from Mice with Latent Tuberculous Infection in the Ex Vivo Model

Tuberculosis is a leading worldwide health problem. The latent, symptom-free stage of tuberculous infection is characterized by the formation of granulomas, specific aggregates of immune cells, predominantly macrophages, containing mycobacteria. The apoptotic death of macrophages containing mycobacteria is considered the main mechanism by which animals and human organisms oppose tuberculous infection and control its development. Previously, we have comparedMycobacterium-host cell relationships in individual granuloma cells from mice with latent tuberculous infection and cells from mouse bone marrow and peritoneal cultures infected with BCG vaccine in vitro and shown that increased death rates were revealed for macrophages heavily loaded with mycobacteria after acute BCG infection in vitro. While in ex vivo cultures granuloma macrophages with large numbers of BCG mycobacteria in them were still viable and had neither apoptotic nor necrotic morphology. Since different specific cellular responses to latent chronic and acute BCG infection in mouse cells were determined, the our aim was to analyze granulomas isolated from the lungs, spleens and bone marrow of Balb/c mice with latent BCG infection for the presence of inducers and markers of apoptotic cell death. In granuloma cells with increased levels of the inducer of apoptosis TNFα, proapoptotic proteins Вах and Ваd, death receptor Fas/ CD95 and scavenge receptor CD36, we did not observe P53 stabilization or caspase-3 activation in the cytoplasm or nuclei of macrophages and dendritic cells, irrespective of the presence or absence of acid-fast BCG mycobacteria in them. The survival receptor CD30 was detected on the cell membranes of only few granuloma macrophages. However, at later times of tuberculous infection in mice, virtually all macrophages and other granuloma cell types had considerable amounts of the antiapoptotic protein Bcl-2 in the cytoplasm and, probably, mitochondria, in contrast to macrophages from bone barrow cell cultures and peritoneal exudates infected with BCG mycobacteria in vitro. Preservation of mitochondrial ΔΨm during staining of living granuloma macrophages containing large amounts of the Bcl-2 protein was indicative of its involvement in maintaining the integrity of mitochondrial elements and the protection of granuloma cells from death, because in similar experiments the control macrophages that did not have any Bcl-2 protein in them had considerably reduced ΔΨm and exhibited morphological signs of apoptotic death. Taken together, our results suggest that the antiapoptotic protein Bcl-2 has been proposed to contribute to the viability of granulomas macrophages not only in ex vivo culture, but also in the animal organism when faced with mycobacterial, proinflammatory and proapoptotic factors operating in granulomatous inflammatory lesions at various times of latent tuberculous infection in mice.

Das thorakale Aortenaneurysma

Thoracic aorta aneurysms are life-threatening diseases which can lead to rupture or dissection due to structural alterations. The exact etiology is still unclear but extended life-expectancy with arterial hypertension, positive family history for aneurysmic diseases, atherosclerosis, smoking and chronic obstructive lung disease are all considered to be risk factors. Nowadays, a diagnosis can often be made in the symptom-free stage. The risk of rupture varies between 46 and 74% for a diameter clearly greater than 5.5 cm and with a 2-year mortality rate of 70%. The 5-year survival rate with conservative treatment can be as low as 13-34% compared to 70-79% after optimal surgical treatment. Medical, operative and percutaneous interventional therapeutic strategies are basically available.

Identification of a novel TTR Gly67Glu mutant and the first case series of familial transthyretin amyloidosis in Hong Kong Chinese

Familial transthyretin amyloidosis (ATTR), caused by mutant transthyretin deposition, is mainly characterized by peripheral neuropathy, autonomic dysfunction, and cardiomyopathy. There are few reports among the Chinese population. We previously described the TTR mutation (Val30Ala) in the first Hong Kong Chinese family with ATTR. In this study, we report the progress of this family and describe another three unrelated Chinese kinships newly diagnosed with ATTR. The second proband presented mainly with peripheral neuropathy, and genetic analysis of the TTR gene showed alanine-to-serine substitution at amino acid 97. The third proband complained of autonomic dysfunction, and a novel missense mutation of glycine-to-glutamate substitution at amino acid 67 was found. The fourth patient presented with peripheral neuropathy and diastolic cardiomyopathy with the mutation threonine-to-lysine at codon 59. Diagnosis was delayed for more than 2 years. We performed DNA analysis in 46 subjects and detected a total of 21 patients, including the four probands, affected with ATTR, 15 of whom were still at a symptom-free stage at the time of writing. We conclude that ATTR remains largely underdiagnosed in the Chinese population. A high clinical suspicion is crucial for a timely diagnosis and can thus lead to a significant decrease in morbidity and mortality.

Intermittent Hydronephrosis Secondary to Ureteropelvic Junction Obstruction: Clinical and Imaging Features

We sought to assess the clinical and imaging findings in intermittent hydronephrosis secondary to ureteropelvic junction obstruction, with particular emphasis on the characteristic ultrasonographic findings. This prospective, longitudinal, observational study included all children who had intermittent ureteropelvic junction obstruction and presented with abdominal pain over 6 years. Renal ultrasound was used as an initial screening tool to detect intermittent hydronephrosis. Renal ultrasonography was repeated every 1 to 2 days to record serial changes from the symptomatic to the asymptomatic stage. Their clinical manifestations and imaging findings were studied. Eighteen patients (14 boys, 4 girls) were studied. Most had sharp pain that began acutely and typically lasted for <2 days. Most of the children (16 of 18) had nausea and vomiting that accompanied the pain. The acute episode generally resolved spontaneously and was followed by a pain-free interval that ranged from days to months. Factors that predisposed to an attack included increased water intake, vigorous exercise, or bladder distention. All patients had clearly demonstrable obstruction of the renal pelvis during an acute attack, a finding that diminished or resolved during the symptom-free intervals. During convalescence, all patients had renal pelvic wall thickening on ultrasonography. This finding appeared on the second or third day after a painful episode subsided, persisted for 6 to 9 days, and then disappeared in the symptom-free stage. Pyeloplasty was performed in 17 patients, none of whom had recurrent pain on follow-up. Extrinsic obstructions were found in 9 patients. The keys to diagnosis are awareness of the syndrome, a detailed history, and immediate and serial imaging studies during painful crises. A thickened renal pelvic wall during convalescence is an important ultrasonic sign of intermittent hydronephrosis.

Clinico-pathological findings of asymptomatic intrahepatic cholangiocellular carcinoma: report of two cases and review of the literature

The prognosis of intrahepatic bile duct carcinoma (cholangiocellular carcinoma: CCC) is extremely poor unless detected at an early and curable stage. However, little is known about the clinico-pathological features of CCC resected at a symptom-free stage. We herein report the clinico-pathological findings in two asymptomatic patients who underwent resection. Their liver function tests showed elevated levels of gamma-glutamyl transpeptidase. An intrahepatic mass was first detected by ultrasonography, and subsequent direct cholangiography and cytological examination revealed the presence of carcinoma in both patients. Left or right hepatic lobectomy with caudate lobectomy and lymph node dissection with or without resection of the extrahepatic bile duct was carried out. The lesions were 2.5 and 2.8 cm in maximal size, originating from the intrahepatic bile duct of segment IV and I, respectively. Both were free from extrahepatic bile duct involvement, intrahepatic and lymph node metastases. However, even in a symptom-free stage, perineural invasion, vascular or lymphatic involvements were histologically proved in both cases, which may be an indication of poor prognosis after surgery alone.

Suppressor T-lymphocytes in the spinal cord of Lewis rats recovered from acute experimental allergic encephalomyelitis

The quantity and distribution of T-lymphocyte phenotypes in the spinal cord of Lewis rats which have recovered from acute encephalomyelitis (EAE) were studied. Lymphoid cells were detected in the spinal cords of all the recovered, asymptomatic rats for periods up to 4 months after recovery. The major difference between the T-lymphocyte populations found in acute EAE compared to the asymptomatic chronic condition was the increase of OX-8 (suppressor) T cells. Thus, the cellular infiltration of the CNS in EAE in the rat appears to be persistent after clinical recovery. Furthermore, the association between OX-8 cells in the spinal cord and the symptomfree stage of the disorder suggests that these suppressor cells exert an effect at the level of the target organ.

Blood gases and acid-base balance in children with bronchial asthma.

Forty-seven children, 1 to 17 years of age, with bronchial asthma were studied on 97 occasions during the symptom-free stage and during episodes of asthmatic symptoms of different degrees. Blood gases and acid-base balance were determined on 39 occasions from capillary blood samples and on 58 occasions from arterial blood samples. During the symptom-free stage, pH, carbon dioxide tension, base excess, standard bicarbonate and arterial oxygen tension remained within normal limits. During asthmatic attacks, the mean pH, base excess and standard bicarbonate were significantly lower than during the symptom-free stage. The mean carbon dioxide tension was normal but varied greatly. Hypoxemia occurred even with very mild signs of asthma and was significantly correlated to the severity of the asthmatic symptoms.

Endorphins in human cerebrospinal fluid: Clinical correlations to some psychotic states

The significance of endorphins, endogenous morphine-like agents, in some psychiatric disorders was investigated. Samples of cerebrospinal fluid were taken by lumbar puncture from healthy volunteers and from patients with schizophrenic, manic-depressive and puerperal psychosis and analyzed for two major fractions of endorphins (Fractions I and II). In 19 healthy volunteers the levels of the two fractions fell within a fairly narrow range. In contrast, six out of nine drug-free and symptom-rich schizophrenics showed elevated levels of Fraction I, which returned to normal or slightly supranormal values after treatment with neuroleptics or propranolol. This decrement was paralleled by a clinical improvement in four of six responding patients. In four manic-depressive patients, serial samples of cerebrospinal fluid revealed elevated endorphin levels, particularly Fraction I during the manic stage. In three out of four patients with puerperal psychosis, the levels of endorphins (either Fraction I or II) were elevated in the acute drug-free stage. During a later symptom-free stage, after treatment with ECT and/or neuroleptics, the endorphin levels were within the normal range. The present data lend credit to the hypothesis that endorphins are involved in some psychotic states in the human.

Pulmonary alveolar microlithiasis

Three cases of pulmonary alveolar microlithiasis are reported at the symptom-free stage of this condition. Two were siblings.

The clinical course of patients with severe “rheumatic” mitral insufficiency

This study has been concerned chiefly with the clinical course of adult patients with predominant rheumatic mitral insufficiency under medical management. It is based on a series of 42 patients followed medically, and a group of 115 patients who underwent cardiac surgery. These have been compared with a group of 138 patients proven to have pure mitral stenosis at surgery. The patients were similar in age and sex. Rheumatic fever had been diagnosed in more than half the patients with insufficiency, and subacute bacterial endocarditis had occurred more frequently, but a history of systemic embolism was less frequent in insufficiency than in stenosis. Strikingly different was the tendency of patients with insufficiency to develop atrial fibrillation and enlargement of the left ventricles and left atria, the latter often very marked. It has been shown that mitral insufficiency may exist in the symptom-free stage for many years, and many of these patients may be in atrial fibrillation and have large and even gigantic left atria, and left ventricular enlargement. Deterioration may be very slow, although sudden death may occur occasionally. The more malignant course and the difference in clinical profile of patients with ruptured papillary muscles or chordae tendineae is described in a group of 13 such patients. The implications of this study in connection with the selection of patients for cardiac surgery have been discussed.

Timed vital capacity in bronchial asthma

1. 1. Eighty-two timed vital capacity measurements were studied in 36 patients with chronic bronchial asthma during (a) the symptom-free stage, (b) “spontaneous attacks,” and (c) experimentally induced attacks of “asthma.” 2. 2. Symptom-free patients had a first second to total vital capacity ratio of 57.5 per cent. There was no significant change of the ratio after medication, although the component parts of timed vital capacity were improved. 3. 3. The patients with spontaneous acute asthma had a first second to total vital capacity ratio of 58.1 per cent. This ratio decreased after the attack was relieved, because of the greater improvement of the total vital capacity rather than of the first second. 4. 4. The patients with experimentally induced “asthma” had a ratio of 52 per cent. The ratio and its response to treatment showed a very close relationship to results obtained in spontaneous asthma. 5. 5. Improvement in the total vital capacity, although subject to some criticism, may be employed as a guide to measure the over-all improvement of the asthmatic patient under treatment. 6. 6. Timed vital capacity and all of its subdivisions represent a valuable technique for the quick estimation of the basic ventilatory disturbances. A decreased ratio of first second vital capacity to total vital capacity, in the presence of a markedly diminished total vital capacity, is a definite indication of the presence of obstructive ventilatory insufficiency. However, the ratio of first second to total vital capacity, considered alone, does not represent a valuable index of the degree of improvement of the asthmatic patient under treatment.