COCCIDIOIDOMYCOSIS—Treatment with Isonicotinic Acid Hydrazide

Since coccidioidal granulomas are histologically indistinguishable from tuberculous granulomas, a long course of isonicotinic acid hydrazide therapy was tried experimentally in three cases of coccidioidomycosis, with good results. In two cases the disease was far advanced and prognosis poor before INH therapy was begun. In one case the disease was mild and symptoms abated after a short course of small doses of INH. It recurred when INH therapy was discontinued, and again resolved when larger doses of INH were given over a longer period.INH seemed to have an effect on appetite also, although the patients were taking B-complex vitamins both before and during INH treatment. The three patients ill with coccidioidomycosis averaged a weight gain of four and a half pounds a month during the period of INH therapy. Six well persons who were underweight and lacked appetite were given INH without other drugs, and they then had an increase in appetite and in weight.     

Disseminated coccidioidomycosis; treatment with ethyl vanillate; a preliminary report

Ethyl vanillate, previously reported to be useful in the treatment of disseminated histoplasmosis, was administered to eight patients with disseminated coccidioidomycosis. Therapeutically effective concentrations of ethyl vanillate were obtained in only three patients, but, in them, the disease was apparently arrested. Failures occurred with patients who were too ill to tolerate the large amounts of ethyl vanillate required to attain a therapeutic concentration in the blood. The principal difficulties of administering ethyl vanillate are (a) the large doses required and (b) the lack of a parenterally administrable form of the drug. Ethyl vanillate, although not universally applicable, may be useful in selected cases of disseminated coccidioidomycosis and should be given further trial.     

Clinical Experience with Vincaleukoblastine Sulfate in the Treatment of 11 Patients with Hodgkin's Disease

Eleven patients with established Hodgkin''s disease were treated with vinblastine sulfate. Each patient received from 0.15 to 0.20 mg./kg. of body weight intravenously in 10 divided doses over a five-hour period as initial therapy. All had received one or more of the more established forms of treatment before being given vinblastine. The response to treatment with vinblastine was excellent in three patients, good in one, and poor in three; there was no response in four. The longest remission was 15 months. Two of the patients were father and son. The side effects of treatment in this series included alopecia, leukopenia, and septicemia.     

Nutritional and pharmacologic support in patients with pancreatic cancer

The aim of our study was to assess whether the influence of nutritional support, consisting of counseling, enteral liquids support and pharmacologic support, can slow down weight loss and whether the change in weight has the impact on the performance status in our patients. In our study 44 patients with pancreatic cancer were included--26 males (mean age 69 years +/- 2.4 years) and 18 females (mean age 63 +/- 3.2 years). Metastatic disease was found in 21 patients, 15 patients had liver metastasis. Locally advanced disease was found in 24 patients and metastatic and locally advanced disease in 17 patients. Surgery was performed in 34 patients. Forty four (100%) patients underwent nutritional counseling, 33 of them (75%) took supplemental enteral feeding and 44 (100%) took megestrol acetate 400 mg per a day. The patients were followed up during 8 weeks during 5 visits. At first visit we took initial nutritional status of patients. Appetite loss, weight gain and Karnofsky performance status were monitored at every visit. All patients were treated with gemcitabin for a 7 week period. Results: NTS score at initial visit in 44 patients (100%) was > or = 5. Using nutritional counseling, enteral food substitution and pharmacological support, weight gain was observed in 61.1% patients and appetite improved. Average KPS mostly improved after first month of therapy while after two months was again at the basal level. With nutritional counseling, supplemental feeding and pharmacologic support weight loss in our patients slowed down and appetite improved. Despite of that, Karnofsky Performance Status didn't change significantly, reflecting the impact of the disease itself and chemotherapy procedures to the patient's condition. We can conclude that nutritional and pharmacological support can temporarily stop weight loss and improve appetite, social life and quality of life in those groups of patients but have no implications on patients KPS and course of their disease.     

Disseminated coccidioidomycosis: clinical,immunologic and therapeutic aspects.

A patient with disseminated coccidioidomycosis initially had pulmonary and skin manifestations and survived for 14 years before dying of meningitis due to Coccidioides immitis. In addition to several courses of amphotericin B therapy the patient received injections of transfer factor derived from appropriate donors and miconazole nitrate therapy. The immunologic defence mechanisms of the patient during the course of his disease were studied and the possibility of a cell-mediated immunologic defect, potentially reversible by transfer factor, was demonstrated.     

Inflammatory and Anti-inflammatory Responses Co-exist Inside Lung Granuloma of Fatal Cases of Coccidioidomycosis: A Pilot Report

Coccidioidomycosis is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. These fungi are endemic in the southern USA and northern Mexico. Immunocompromised patients are susceptible to develop severe forms of this fungal infection. Cytokines play an important role in controlling the fungal infection, but little is known about the predominant immunological environment in human lung tissue from fatal cases. Our aim was to analyze the pro-inflammatory and anti-inflammatory cytokines and monocyte/macrophages markers (CD14 and CD206) in the granulomas of six fatal cases of coccidioidomycosis. Cytokines and surface markers were higher in coccidioidomycosis cases when compared to control (P?<?0.05). CD14 positive cells were increased inside the coccidioidal granuloma when compared to the outside (P?<?0.05). No differences were found in the number of CD206+ cells inside the granuloma when compared to the outer population (P?>?0.05). Interestingly, an analysis of stain intensity signals showed an increased signaling of CD14, CD206, IL-10 and TNFα inside the granuloma when compared to the outside (P?<?0.05). iNOS and IL-12 gene expression were not detected in coccidioidomycosis cases, while IL-10, IL-6 and TGFβ gene expression were detected, but the differences when compared to healthy lungs were not significant (P?>?0.05). TNFα gene expression was lower in coccidioidomycosis cases when compared to healthy lung (P?=?0.05). In conclusion, pro- and anti-inflammatory responses co-exist inside of the granulomas of fatal cases of coccidioidomycosis and the absent of iNOS and IL-12 gene expression may be related with patient’s outcome.     

COCCIDIOIDOMYCOSIS AS A COMPLICATION OF PREGNANCY

Records of 33 cases of coccidioidomycosis occurring during pregnancy were reviewed. In this group the incidence of dissemination of the disease was considerably greater than the reported incidence of dissemination in all cases of coccidioidomycosis.The incidence of dissemination was higher in the patients who contracted coccidioidomycosis late in pregnancy than it was in those in whom onset of the disease occurred earlier in gestation; but dissemination occurred in all Negro patients in the group, regardless of the time of onset during pregnancy.The chief complicating effect when onset was in the first trimester of pregnancy was a tendency to abortion. In cases in which onset was in the third trimester, the incidence of premature labor was extremely high.There was no evidence of congenital infection in any of the babies, but in one case invasion of the placenta by coccidioidal spherules was observed.     

In Canada: A Trial of Chemoprophylaxis in Inactive Tuberculosis

One thousand five hundred and thirty-six patients with inactive tuberculosis were given a course of preventive treatment consisting of either INH alone or INH and PAS while 840 similar patients served as a control group. Discontinuation of the treatment was frequent and was usually caused by development of complaints which the patients ascribed to the drugs they were taking.The annual reactivation rate among controls was 4.9 per 1000. During the period of taking drugs the treated group suffered a reactivation rate of 0.7 per 1000 and those who had taken the medication for at least six months suffered a subsequent annual reactivation rate of 1.3 per 1000. The rate for those who discontinued treatment in the first six months was 5.1 per 1000. There were no reactivations in patients who took INH and PAS for over six months. Bacilli from two of the patients with reactivations who were treated for a prolonged period with INH alone showed resistance to this drug.Chemoprophylaxis of inactive cases is a potent weapon in tuberculosis control; however, it requires thorough motivation and supervision.     

Metformin Decreases Food Consumption and Induces Weight Loss in Subjects with Obesity with Type II Non-Insulin-Dependent Diabetes

Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3times3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity.     

Coccidioidomycosis: Evaluation of parameters used to predict outcome with amphotericin B therapy

A literature review of case histories describing the use of amphotericin B for the treatment of disseminated coccidioidomycosis was performed to detect parameters that were predictive of therapeutic outcome. Several factors were significantly different between patients who were well during prolonged follow-up versus those with active or recurrent disease: 1) mean complement fixation (CF) titer before treatment was lower in patients who were well; 2) well patients had a greater magnitude fall in CF titer during amphotericin B therapy; 3) mean CF titer after amphotericin B treatment was lower in patients who were well; and 4) patients with a positive coccidioidin skin test before therapy were more likely to be well at 6 months. There was no correlation between total amphotericin B dose or duration of therapy and therapeutic outcome.     

Coccidioidomycosis: An Update

Coccidioidomycosis is the oldest of the major mycoses. In recent years the incidence of the disease has increased in California and Arizona, which may be partially due to the massive migration to the endemic region. The endemic region for the disease lays exclusively in the Western Hemisphere, between the 40° latitudes north and south. The disease manifests in one of four clinical syndromes: acute pulmonary, chronic pulmonary and acute or chronic disseminated coccidioidomycosis. Serologic tests identifying anticoccidioidal antibodies are the most frequently employed assays for diagnosis. Primary coccidioidomycosis is usually self-limited; therapy of primary disease is recommended when symptoms persist for more than 6 weeks, for severe acute cases and for patients with impaired cellular immunity. Chronic pulmonary coccidioidomycosis and all forms of disseminated coccidioidomycosis require antifungal therapy. The drugs of choice are either fluconazole or itraconazole.     

Regenerative ability of hepatocytes is inhibited in early stages of liver fibrosis.

Female Wistar rats were given three doses of carbon tetrachloride, 10.4 mmol/kg of body weight. The doses were administered within 16 days and another 16 days were allowed to pass before partial (37%) hepatectomy was done. The liver showed very mild fibrosis at that time. DNA synthesis (measured by 3H-thymidine incorporation) was decreased by 53% and mitotic activity of hepatocytes was decreased by 56% when compared to olive oil-pretreated partially hepatectomized controls. The results show that the mitotic potential of hepatocytes in early stages of liver fibrosis is impaired which may influence the course of the disease.     

RESULTS OF LONG-CONTINUED CORTISONE ADMINISTRATION IN RHEUMATOID ARTHRITIS

The administration of cortisone acetate to patients with rheumatoid arthritis usually produces prompt and often dramatic suppression of the disease manifestations. The effects of the hormone are not lasting, however, and after withdrawal relapse ensues. For sustained improvement in a chronic disease such as rheumatoid arthritis, it appears that cortisone must be given more or less continuously. This raises the question whether administration may be continued effectively and safely for long periods.Seventy-six patients with rheumatoid arthritis were given cortisone in the hope that treatment could be continued uninterruptedly for extended periods. For various clinical reasons it was necessary to discontinue treatment in 16 of these before six months, but the remaining 60 patients received the hormone uninterruptedly for six to 15 months. By using initial large suppressive amounts, then gradually reducing the dosage, and finally employing smaller maintenance doses, adequate degrees of rheumatic control were maintained in approximately two-thirds of the original 76 patients. The ability to sustain satisfactory improvement varied indirectly, in general, with the severity of the rheumatoid arthritis. The chief detriment to better results in the more severe cases was the intervention of adverse hormonal side effects which developed frequently when large or relatively large maintenance doses were required to support satisfactory improvement.Unwanted signs of hormonal excess developed in 40 per cent of cases at some time during the course of treatment. Most of them were mild or transient and disappeared or lessened when the dose of cortisone was reduced, but when the dose was reduced the degree of improvement often declined also.During prolonged cortisone therapy evidence of functional suppression of the adrenal cortices, as indicated by a decreased response of circulating eosinophils to exogenous ACTH, was present. The depression of cortical function was temporary, however. Whether irreversible damage may result when the drug is employed for longer periods cannot yet be answered.     

An outbreak of blastomycosis in Eastern Tennessee

Most cases of blastomycosis are sporadic and only nine outbreaks representing a total of 112 cases have previously been reported. Less than half of these have been culture proven cases. Outbreaks have previously occurred in North Carolina, Minnesota, Illinois, Wisconsin and Virginia. We report three culturally confirmed cases of blastomycosis from Elizabethton, Tennessee, who had onset of illness within a one-week span of time. The patients presented with fever, chest pain, weight loss, poor appetite and myalgia. Each initially had a dry cough which became productive of purulent sputum as the illness progressed. Mild hemoptysis occurred during each patient's course. Serologic testing by immunodiffusion and enzyme immunoassay were positive and testing by complement fixation was negative in each case. The diagnosis was made by histopathology on transbronchial biopsy or transthoracic needle aspiration material. Each patient improved on ketoconazole therapy.     

Identification of coccidioidomycosis of the lung by fine needle aspiration biopsy

A solitary coin lesion in the lung is a frequent presentation of coccidioidomycosis; these lesions may be radiologically indistinguishable from cancer. In a series of 112 fine needle aspiration (FNA) biopsies performed in the San Joaquin Valley on solitary pulmonary nodules, 8 cases were identified as coccidioidomycosis by the presence of spherules in the aspirated material. The immature sporangia ranged in size from 4 micron to 40 micron. The smaller spherules did not show endospores and could have been confused with red blood cells. A methenamine silver or periodic acid-Schiff stain was helpful in identifying the spherules following decolorization of Papanicolaou-stained material; this was especially important when the background material was bloody. Older nonviable spherules showed a folded collapsed cell membrane, which may be associated with long-standing cavitary disease. A complement fixation titer was frequently not elevated. This study demonstrates the utility of FNA biopsy in the identification of cocci granulomas in the lung.     

Circadian mesor of recumbent pulse--cost-effective predictor of doxorubicin-induced congestive heart failure

Nineteen adult cancer patients each received 6-10 monthly treatments of doxorubicin and cisplatin. For 24-30 hr before each treatment, recumbent pulse was measured. Treatment was stopped for disease progression or when a total doxorubicin dose of 550 mg/m2 was reached. No patient developed congestive heart failure (CHF) during therapy. Two to four months after stopping treatment, three patients developed CHF. In these cases, 2-6 months before complication of therapy, prior to notable decrement in any other index of cardiac function, the 24-hr rhythm-qualified mean (mesor) of pulse showed a positive slope by linear regression analysis (P less than 0.05). This mesor rise was apparent at cumulative doxorubicin doses of 300, 420 and 240 mg/m2. patients subsequently received additional doxorubicin to total doses of 540, 525 and 530 mg/m2. Patients who did or did not experience a rise in pulse received similar total doses of doxorubicin. Serial pulse mesors predicted CHF reliably and were substantially less expensive than radionuclide ejection fraction determination ($200 per test). A progressive rise in the circadian pulse-mesor was clearly a harbinger of histologically documented doxorubicin-induced lethal CHF in Wistar-Kyoto rats of both sexes.     

Disseminated coccidioidomycosis in a heart transplant recipient

A cardiac transplant patient developed disseminated coccidioidomycosis shortly after transplantation and institution of immunosuppressive therapy. The patient was maintained on intravenous and intrathecal amphotericin B for 19 months, but when therapy was discontinued, the disease relapsed and he died. At autopsy the cardiac allograft was without signs of rejection, but the patient had coccidioidomycotic lesions in multiple organs. There is an increasing number of reports of disseminated coccidioidomycosis in immunocompromised patients, especially those who receive steroids or immunosuppressive therapy. Coccidioidomycosis may represent a severe complication in the transplant patient.     

Aerosolized interferon-alpha treatment in patients with multi-drug-resistant pulmonary tuberculosis

Multi-drug-resistant tuberculosis (MDR-TB) has emerged as an obstacle to the control of tuberculosis. Recent data however, suggest that interferon-(IFN)-gamma and IFN-alpha may improve disease evolution in subjects affected with pulmonary tuberculosis caused by multi-resistant (IFN-gamma) and sensitive (IFN-alpha) strains. The mechanisms involved are not known, even though it has been reported that IFN-gamma-secreting CD4+ Th cells may possess antitubercular effects. In addition, IFN-alpha can induce IFN-gamma secretion by CD4+ Th cells, and both types of IFN may stimulate macrophage activities. The aim of this study was to explore the possibility that aerosolized IFN-alpha, administered concomitantly with conventional antitubercular chemotherapy, may improve the course of pulmonary tuberculosis. After six months of directly observed therapy (DOT), seven patients who were non-responders to a second line antitubercular therapy were given an IFN-alpha aerosol (3 MU, three times a week) for two months as adjunctive therapy. All strains were resistant to at least two first-line drugs. After IFN-alpha administration, the patients were followed up for a further six months with the same DOT. Sputum samples were collected monthly during the study period, with the exception of the IFN-alpha administration period, when the observations were performed weekly. High resolution computed tomography (HRCT) chest scans were performed before and after IFN-alpha inhalations. The analysis of the results showed that the mean number of Mycobacterium tuberculosis (Mt) had remained statistically unchanged (p = 0.80) during the first 6 months of DOT. During the following 2 months of IFN-alpha administration, 5 patients became negative (p = 0.02). After the end of treatment a progressive increase in Mt number was observed (p = 0. 02). Sputum cultures remained positive for all patients throughout the study period, although a significant decrease (p = 0.02) in the colony number per culture was observed after adjunctive treatment with IFN-alpha. After stopping administration of IFN-alpha, a significant increase (p = 0.03) in the colony number per culture was noted as well as in Mt numbers. HRCT scans were slightly improved in all patients. These preliminary data suggest that aerosolized IFN-alpha may be a promising adjunctive therapy for patients with MDR-TB. Optimal doses and schedules however, require further studies.     

Elevation of Brain GABA Content by Chronic Low-Dosage Administration of Hydrazine, a Metabolite of Isoniazid

Abstract: When γ-aminobutyric acid aminotransferase (GABA-T) activity was measured in vitro in rat brain, neither isoniazid (INH) nor four of its known metabolites (isonicotinic acid, acetylisoniazid, acetylhydrazine, diacetylhydrazine) inhibited the enzyme in concentrations (5 mM) far higher than those likely to be achieved when INH is administered to man. In contrast, hydrazine (5 μM) caused a 50% inhibition of GABA-T without inhibiting glutamic acid decarboxylase (GAD). Rats were injected daily for 109 days with hydrazine (0.08 or 0.16 mmol/kg/day), after which amino acid contents and enzyme activities were measured in their brains. Both hydrazine doses caused significant elevations of whole brain GABA content and reductions of GABA-T activity, but did not affect GAD activity. Chronic administration of hydrazine at thee doses did not reduce weight gain or alter rat behavior, nor did it produce any irreversible pathologic changes in liver or alterations in hepatic aryl hydrocarbon hydroxylase activity. However, hydrazine treatment caused changes in the contents of many brain amino acids besides GABA, and markedly increased concentrations of ornithine, tyrosine, and α-aminoadipic acid in rat plasma. Inhibition of GABA-T activity and the other biochemical alterations observed in patients given high doses of INH probably result from hydrazine formed in the metabolic degradation of INH. Thus administration of hydrazine might be a more direct means of elevating brain GABA content in patients where this seems indicated, and might not entail a greater risk of adverse effects.     

Treatment of hepatic hydatid disease with mebedazole: preliminary results in four cases.

Mebendazole was given to four patients with hepatic hydatid disease. In three patients hydatidosis had remained after surgery, and in the fourth it could not be treated surgically. Mebendazole was given orally in maximum doses of 400-600 mg three times a day during courses lasting 21 to 30 days. Ultrasonic echotomography showed a complete regression of the intrahepatic cysts after four to 13 months in all four cases. In three patients the course of treatment had to be repeated. Mebendazole also induced clinical improvement and a progressive lowering of the concentration of specific IgE of Echinococcus granulosus. During treatment circulating blood levels of specific immune complexes of antigen 5 were increased. These observations indicate that mebendazole has a lethal effect on E granulosus cysts in primary hydatid disease in man and that the efficacy of chemotherapy can be assessed with ultrasonography and by measuring changes in the concentration of specific IgE of E granulosus and circulating immune complexes.