Neurological form of cryptococcosis. Apropos of 2 atypical cases in non HIV-infected patients

Cryptococcal infection is the most common fungal infection of the central nervous system. More than 50% of the cases of cryptococcal infection are superimposed on an immunosuppressive or other general debilitating condition. Cerebral cryptococcosis usually presents as meningitis or meningoencephalitis, although cerebral granuloma has also been reported. Hydrocephalus is the most common neurosurgical complication of cerebral cryptococcosis. The majority of patients require only medical treatment with antifungal drugs. However, when complications ensue, surgical intervention is mandatory. We suggest that chronic meningitis be ruled out in all patients prior to the placement of shunts. In the two cases reported here treatment of cryptococcal meningitis was a combination of amphotericin B and flucytosine for six weeks. Fluconazole is a new alternative and at least as effective as amphotericin B.     

Combination therapy with fluconazole and flucytosine in the murine model of cryptococcal meningitis

This study elucidates the role of combined fluconazole and flucytosine as therapy for cryptococcosis in the murine model of meningitis. Three strains of Cryptococcus neoformans for which the range of fluconazole MICs was wide--2 microg/ml (susceptible strain), 8 microg/ml (moderately susceptible strain), and 32 microg/ml (resistant strain)--were used for infection. One day postinfection, the mice were randomized into eight treatment groups: placebo; flucytosine (40 mg/kg of body weight/day); fluconazole at 3 mg/kg/day (low dosage), 10 mg/kg/day (moderate dosage), or 20 mg/kg/day (high dosage); and combined flucytosine and fluconazole at low, moderate, or high doses of fluconazole. Three major findings were demonstrated: (i) correlation between the MICs for the isolates and the in vivo effectiveness of fluconazole as assessed by the reduction in cryptococcal brain burden, (ii) a dose-response curve (a higher dose of fluconazole was significantly more efficacious than a lower dose [P < 0.001]), and (iii) synergism between fluconazole and flucytosine (therapy with a combination of fluconazole and flucytosine was superior to therapy with either agent alone [P < 0.01]).     

Laparoscopic cholecystectomy during pregnancy is safe for both mother and fetus

The use of laparoscopic cholecystectomy in pregnant women has been slow to gain wide acceptance for two reasons: one is the potential for mechanical problems related to the pregnant uterus and the other is fear of fetal injury resulting from instrumentation or the pneumoperitoneum. To assess the effects of laparoscopic cholecystectomy on both the mother and the unborn fetus, we reviewed our surgical experience over a 5-year period analyzing indications for the procedure along with complications and outcome. During this 5-year period, 22 patients ranging in age from 17 to 31 years underwent laparoscopic cholecystectomy during pregnancy. Gestational ages ranged from 5 to 31 weeks with two patients being in the first trimester, 16 in the second, and four in the third. The primary indications for surgical intervention were persistent nausea, vomiting, pain, and inability to eat in 17 patients, acute cholecystitis in three, and choledocholithiasis in two. In all patients a pneumoperitoneum was established by means of a closed technique starting in the right upper quadrant of the abdomen. Two of the 22 patients also underwent successful transcystic common bile duct exploration with removal of common duct stones. All 22 patients survived the surgical procedure without complications, and there were no fetal deaths or premature births related to the procedure. Based on the preceding results, it would appear that laparoscopic cholecystectomy during pregnancy is safe for both the mother and the unborn fetus. Indications for this procedure should include stringent criteria such as unrelenting biliary tract symptoms or the complications of cholelithiasis. If at all possible, when laparoscopic cholecystectomy is indicated, it should be performed either in the second trimester or early in the third.     

Differential expression of plasma membrane calcium pump mRNA isoforms in rat osteoblast-like cells

Cryptococcal meningitis is a common infection in patients with AIDS. Using a murine cryptococcosis model, we compared treatment with a new triazole, D0870, and fluconazole. Groups of ICR (Institute for Cancer Research) mice were infected intracerebrally with eight different isolates of Cryptococcus neoformans variety neoformans with different in vitro susceptibilities to fluconazole. For survival studies mice were challenged with two to four times LD(50) or six to nine times LD(50). Treatment was given for 10 days. Mice were observed through to day 30. To assess the effect of treatment on fungal tissue burden, mice received a three to five times LD(50) inoculum and treatment for 10 days. They were sacrificed on day 12 and serial dilutions of brain homogenates were cultured. Fluconazole prolonged survival primarily in isolates which were susceptible in vitro. D0870 prolonged survival in all isolates except one, which was also resistant in vitro to D0870 and fluconazole. Both drugs reduced colony counts of all isolates. D0870 warrants further development for use in cryptococcosis, and appears effective for isolates relatively resistant to fluconazole. There is a relative correlation of in vivo and in vitro susceptibility to D0870 as well as fluconazole.     

Effects of beta-adrenoceptor-blockade on stress-induced adrenocorticotrophin release in humans

A six-year-old, male Doberman pinscher was presented for acute onset of upper motor neuron tetraparesis. An extradural compressive lesion compatible with intervertebral disk rupture at the sixth to seventh cervical (C6-C7) disk space was evident on myelography. A large, gelatinous mass of pure cryptococcal organisms causing spinal cord compression was identified upon exploratory surgery. Removal of the mass caused relief of clinical signs. No evidence of involvement of other organ systems was found; however, serum and cerebrospinal fluid titers were positive for cryptococcal infection. The dog was treated with fluconazole (5.5 mg/kg body weight, per os sid) until serum titers for cryptococcal infection were negative at seven months postsurgery. To the authors' knowledge, this is the only report of a dog with cryptococcosis treated successfully using fluconazole as a sole agent.     

206 cases of spinogenic dizziness treated by contralateral acupuncture

The case of an 18-year-old pregnant woman with cryptococcal meningitis treated with amphotericin B and flucytosine since the third trimester of pregnancy is reported. She delivered a normal baby. The maternal outcome was favorable. There is no evidence of congenital infection in the newborn.     

Use of cerebrospinal fluid shunts in patients having acquired immunodeficiency syndrome with cryptococcal meningitis and uncontrollable intracranial hypertension

OBJECTIVE: To evaluate the treatment of serious and uncontrollable intracranial hypertension in patients with acquired immunodeficiency syndrome who developed cryptococcal meningitis. METHODS: All cases of cryptococcal meningitis with elevated pressure and acquired immunodeficiency syndrome were reviewed in detail and described. RESULTS: Cerebrospinal fluid shunting dramatically improved these critically ill patients and was much more successful than serial lumbar punctures or the use of high-dose dexamethasone. CONCLUSION: Patients with acquired immunodeficiency syndrome who develop cryptococcal meningitis and who suffer serious visual loss or ocular palsies with elevated pressures should be considered for cerebrospinal fluid shunting at an early stage.     

Fluconazole. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients

Fluconazole is a triazole antifungal agent which is now an established part of therapy in patients with immune deficiencies. It is effective against oropharyngeal/oesophageal candidiasis (candidosis) when used orally once daily either as treatment or secondary prophylaxis in patients with AIDS or as treatment or primary prophylaxis in neutropenia associated with cancer therapy. Fluconazole also resolves symptoms in up to 60% of patients with cryptococcal meningitis and AIDS. However, in this infection its efficacy as treatment relative to that of amphotericin B is equivocal, and its major role is as the drug of choice for maintenance therapy following amphotericin B induction. In this regard, fluconazole has been proven superior to amphotericin B and to itraconazole 200 mg/day. Comparisons with other drugs used for the treatment of mucosal candidiasis in patients with AIDS show fluconazole to be superior to nystatin, similar to itraconazole and at least as effective as clotrimazole and ketoconazole; it was more so than the latter azole in 1 study. In patients undergoing chemotherapy or bone marrow transplantation, fluconazole as primary prophylaxis has produced greater clinical benefit than a clotrimazole regimen. The incidence of adverse events appears to be somewhat higher in patients with AIDS compared with HIV-negative cohorts, but the qualitative pattern of events is similar. The most frequent events are gastrointestinal complaints, headache and skin rash: rare exfoliative skin reactions and isolated instances of clinically overt hepatic dysfunction have occurred in patients with AIDS. Issues yet to be clarified include: the use of fluconazole in children with AIDS, in whom results have been promising; its efficacy against other fungal infections encountered in immunocompromised patients; whether the drug influences mortality, as has been suggested by one placebo-controlled trial in patients undergoing bone marrow transplant; and the appropriateness of its potential for use as primary prophylaxis against cryptococcal meningitis in patients with AIDS, where it shows efficacy but there is concern over increasing risk of development of secondary resistance. Notwithstanding these undefined aspects of its clinical profile, fluconazole is now confirmed as an important antifungal drug in the management of fungal infections in patients with immune deficiencies. In patients with AIDS it is the present drug of choice as maintenance therapy against cryptococcal meningitis and is a preferred agent for secondary prophylaxis against candidal infections; it is also a favoured agent for primary prophylaxis in patients at risk because of neutropenia associated with chemotherapy or bone marrow transplantation .     

Food advertising on British children''s television: a content analysis and experimental study with nine-year olds

No unanimous consent has been reached about treatment guidelines of cryptococcosis in the setting of AIDS, as well as about optimal fluconazole dosing in both initial and suppressive therapy. In order to evaluate the relationship between fluconazole dosing and clinical and microbiological outcome of AIDS-related cryptococcosis, a retrospective study was carried out on 30 consecutive patients. Among the 12 subjects treated with fluconazole doses < 400 mg/day, an unfavorable course was significantly more frequent (early mortality, poor clinical and microbiological response, appearance of early relapses) compared with the 18 patients who received daily doses > or = 400 mg, while no differences were observed between the two treatment groups according to known risk factors for a poor prognosis. When assessing maintenance treatment (22 evaluable cases), the 15 patients receiving oral fluconazole at doses < 200 mg/day showed earlier disease relapse and mortality as opposed to the 7 individuals treated with high-dose fluconazole (> or = 200 mg/day), in the absence of significantly different risk factors for disease recurrence. Our experience pointed out a significant difference in clinical activity of fluconazole in AIDS-related cryptococcosis according to its daily dosing, and suggested 400 and 200 mg as the threshold daily dose for an effective initial and suppressive therapy, respectively, since the probability of treatment failure seemed greater with low-dose drug administration, after controlling data for prognostic markers of disease severity. Controlled studies are warranted, comparing high-dose fluconazole with standard regimens containing amphotericin B in the treatment of AIDS-associated cryptococcosis, and identifying the best fluconazole dosing for both acute-phase and maintenance treatment.     

In vitro and in vivo efficacy of the triazole TAK-187 against Cryptococcus neoformans

Multiple isolates of Cryptococcus neoformans, including those with fluconazole resistance, were tested to assess the in vitro activity of the new triazole TAK-187. MICs of TAK-187 were at least eightfold lower than those of fluconazole, and fungicidal concentrations for most isolates were 4 microg/ml or less. TAK-187 also was evaluated as intermittent therapy using two dosages in a rabbit model of experimental cryptococcal meningitis. Compared to daily treatment with fluconazole, as little as two doses of TAK-187 given 7 days apart were found to be effective. Plasma and cerebrospinal fluid TAK-187 concentrations were many times higher than MICs and fungicidal concentrations. Based upon its therapeutic efficacy and long half-life in the rabbit model, TAK-187 should be investigated for intermittent dosing in treatment or suppression of cryptococcal infections in humans.     

Candidal meningitis in HIV-infected patients: analysis of 14 cases

Five cases of candidal meningitis in human immunodeficiency virus (HIV)-infected patients have been diagnosed in our hospital. This article describes these cases and reviews another nine previously reported in the literature. Most patients (71%) had at least one well-known predisposing factor for candidiasis. Median CD4 cell count was 135/mm3. Headache and fever, in the absence of focal neurologic signs, were the predominant clinical features. The CSF analysis revealed mild pleocytosis and hypoglycorrachia, indistinguishable from those seen in tuberculous or cryptococcal meningitis. Twelve patients (92%) received amphotericin B for a median of 51 days, in combination with flucytosine in five cases. The overall mortality among treated patients was 31%. Although the risk of relapse of candidal meningitis is unknown, maintenance antifungal therapy was given to seven patients (63%), usually with fluconazole. Candida species must be kept in mind as a cause of chronic meningitis in HIV-infected patients who have a known predisposing factor.     

The development of maternal-fetal attachment during pregnancy

This study is to examine the degree to which women engage in attachment behaviors toward their unborn children. Cranley's Maternal-Fetal Attachment Scale (MFAS) was modified to Japanese version (MFAS-J2), which consists of 20 items with .87 reliability. MFAS-J2 was administered to both normal and high-risk pregnant women (n = 275) during gestation. All subjects were restricted to women who were having their first child, and they were between 5 and 40 weeks gestation at the time they completed the instrument. Demographic data were also gathered. Results: (1) Maternal-fatal attachment increased significantly from 5 to 40 weeks of gestation. Especially feeling fetal movement had positive effect on maternal-fetal attachment. (2) Women who reported negative perception or ambivalent feeling about their pregnancy showed low attachment score. And women whose husband reported negative feeling about their pregnancy responded lower in the scale. (3) Some negative relationships were observed between maternal-fetal attachment score and the histories of abortion and sterility. (4) Maternal-fetal attachment showed no significant correlations to factors of threatened abortion, premature labor, and IUGR. (5) Maternal-fetal attachment showed negative correlations to State-Trait anxiety during early pregnancies.     

Treatment of inflammatory rheumatic disorders in pregnancy: what are the safest treatment options?

The interaction of pregnancy and the rheumatic diseases varies, ranging from life-threatening conditions such as thromboembolic events and progressive renal disease in some autoimmune disorders, to minor flares of peripheral arthritis in inflammatory rheumatic disease. As a consequence, treatment strategy will vary according to the maternal or fetal compromise expected. All nonsteroidal anti-inflammatory drugs (NSAIDs), including high dose aspirin (acetylsalicylic acid), can cause adverse effects during pregnancy related to the inhibition of prostaglandin synthesis. Prolongation of gestation and labour, constriction of the ductus arteriosus, persistent fetal circulation, impairment of renal function and bleeding are risks of third trimester exposure of pregnant women to all inhibitors of cyclo-oxygenase. Most of these adverse effects can be prevented by discontinuing NSAIDs 8 weeks prior to delivery. Low dose aspirin has not been associated with fetal or neonatal toxicity. Some corticosteroids such as prednisone and prednisolone do not readily cross the placenta and can be safely used during pregnancy as immunosuppressive drugs. Maternal complications related to corticosteroids may occur and close monitoring is therefore mandatory. There is limited information on the safety of disease-modifying antirheumatic drugs including gold, antimalarials, penicillamine (D-penicillamine), sulfasalazine and cyclosporin. Of these agents, sulfasalazine has the best record for tolerability and can be used by pregnant patients. Gold compounds and penicillamine should be discontinued when pregnancy is recognised. Hydroxychloroquine has not been associated with congenital malformations and seems preferable to chloroquine in patients requiring treatment with antimalarials. Use of cyclosporin may be an alternative to other therapy in pregnant patients with severe rheumatic disease. Indications for treatment with colchicine during pregnancy are few, except for familial Mediterranean fever. Azathioprine can be used when the maternal condition requires a cytotoxic drug during the first trimester. Cyclophosphamide, chlorambucil and methotrexate are contraindicated during pregnancy because of their teratogenic potential. Their use may be considered in late pregnancy if the mother has a life-threatening condition.     

Acute neonatal respiratory distress in Italy: a one-year prospective study. Italian Group of Neonatal Pneumology

We treated two cases of primary pulmonary cryptococcosis with fluconazole (FLCZ), the clinical usefulness of FLCZ was evaluated. FLCZ was administered orally in doses of 300 mg daily for about six months. Concentrations of FLCZ were measured in the serum of the two cases and in the bronchoalveolar lavage (BAL) fluid in one case. The following results were obtained: 1. Clinical cures were obtained in the two cases. 2. The serum levels of FLCZ was 15.1 microliters/ml, 13.6 micrograms/ml two hours after administration of 100 mg in case 1, that of levels were 11.1 micrograms/ml, 8.9 micrograms/ml one hour and 4.5 hours, respectively, after administration of 100 mg in case 2. BAL was performed 4.5 hours after administration of 100 mg in case 2, the BAL fluid level of FLCZ was 0.7 microgram/ml. 3. The minimal inhibitory concentration of FLCZ against one strain obtained from the cytology brush in case 1 was 4.0 micrograms/ml. 4. The cryptococcal antigen titer decreased with the improvement of clinical signs and the resolution of chest X-ray abnormalities within about six months, and there was no relapse. From these results, we consider that FLCZ is a useful antifungal agent for primary pulmonary cryptococcosis, and we therefore recommend a six month treatment.     

Pregnancy in patients with cystic fibrosis

With increasing life span of patients with CF, more women with CF are becoming pregnant and others are seeking information about the risks involved during pregnancy and delivery. A striking limitation of the available information is the lack of large prospective studies of pregnant patients with CF matched for age and disease severity compared with their non-pregnant cohorts. A study investigating the effect of pregnancy on morbidity and mortality is being completed by the Cystic Fibrosis Foundation. We recommend that all women with CF be offered contraceptive measures and counseling on the maternal and fetal risks of pregnancy, including the genetic risks for the child. The issue of who will raise the child in the event of subsequent morbidity or maternal mortality should ideally be prospectively discussed.     

Periodic health examination, 1996 update: 2. Screening for chlamydial infections. Canadian Task Force on the Periodic Health Examination

OBJECTIVE: To update the 1984 recommendations of the Canadian Task Force on the Periodic Health Examination on the routine screening of asymptomatic patients for infection with Chlamydia trachomatis. OPTIONS: Screening, with the use of culture or nonculture tests, of the general population, of certain high-risk groups or of all pregnant women; or no routine screening. OUTCOMES: Rates of asymptomatic and symptomatic chlamydial infection, perinatal complications, longterm complications of infection (i.e., pelvic inflammatory disease, infertility and ectopic pregnancy), coinfection with other sexually transmitted diseases, disease spread, hospital care, complications of therapy and costs of infection and of screening. EVIDENCE: Search of MEDLINE for articles published between Jan. 1, 1983, and Dec. 31, 1995, with the use of the major MeSH heading "chlamydial infections," references from recent review articles and recommendation by other organizations. VALUES: The evidence-based methods of the Canadian Task Force on the Periodic Health Examination were used. Advice from reviewers and experts and recommendations of other organizations were taken into consideration. Prevention of symptomatic disease and decreased overall costs were given high values. BENEFITS, HARMS AND COSTS: The greatest potential benefits of screening asymptomatic patients for chlamydial infections are the prevention of complications, especially infertility and perinatal complications, and the prevention of disease spread. There is no evidence that screening of the general population for chlamydial infections leads to a reduction in complications, and screening may increase costs. However, there is evidence that annual screening of selected high-risk groups and of pregnant women during the first trimester is beneficial in preventing symptoms and reducing the overall cost resulting from infection. RECOMMENDATIONS: There is fair evidence to support screening and treatment of pregnant women during the first trimester (grade B recommendation) as well as annual screening and treatment of high-risk groups (sexually active women less than 25 years of age, men or women with new or multiple sexual partners during the preceding year, women who use nonbarrier contraceptive methods and women who have symptoms of chlamydial infection: cervical friability, mucopurulent cervical discharge or intermenstrual bleeding; grade B recommendation). There is fair evidence to exclude routine screening of the general population (grade D recommendation). VALIDATION: These recommendations are similar to those of the US Preventive Services Task Force and the US Centers for Disease Control and Prevention, Atlanta. SPONSOR: These guidelines were developed and endorsed by the Canadian Task Force on the Periodic Health Examination, which is funded by Health Canada and the National Health Canada and the National Health Research and Development Program. The principal author (H.D.D.) was supported in part by the Ontario Ministry of Health and the Canadian Infectious Diseases Society Lilly Fellowship.     

Pre-eclampsia and its psychosocial sequelae

In the present work some psychosomatic conditions in the setting of preeclampsia are described. The important psychosocial consequences for women suffering from this disease and the drawback for their partners will be elucidated. Preeclampsia as a disease including hypertension, proteinuria and generalized edema is often associted with generalized seizures occuring most commonly at the end of the second trimenon of pregnancy. The disease bears a heavy risk for the mothers as well as for her unborn child. Until now the exact pathophysiological basis of the disease has not been entirely elucidated. For the pregnant woman and her psychosocial surrounding the outbreak of the disease is in most cases unexpected. During development of the disease she has to face a role change from a so far normal pregnancy to a high-risk situation. This may change also the attitude to the unborn child by herself and her partner. The preterm delivery induced therapeutically, together with the succeeding problems for the newborn complete the high psychosocial stress related to the entire situation. Therefore it is useful and important to offer psychosocial support to the mother as well as to her parter during the illness and the time after delivery.     

Comparison of supercritical fluid extraction and conventional liquid-solid extraction for the determination of benzo[a]pyrene in water-soluble smoke

In patients undergoing bone marrow transplantation cryptococcosis is rarely encountered. We report a fatal case of Cryptococcus meningitis in a 12-year-old girl with acute lymphoblastic leukemia (ALL) in second remission who had a transplant from a human leukocyte antigen (HLA)-identical unrelated bone marrow donor. The conditioning regimen was thiotepa, cyclophosphamide, and total body irradiation (TBI); graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A, methotrexate, and antilymphocyte globulin (ALG). The patient experienced stage III GVHD responsive to high-dose corticosteroids. On day +54 a thrombotic microangiopathy occurred. On day +64 neurological status worsened; a brain computed tomographic (CT) scan showed hyperdense lesions suggesting fungal infection. Detection of cryptococcal antigen by latex agglutination was positive but India ink stain and culture were negative. Despite treatment with amphotericin B, 5-flucytosine, and granulocyte-macrophage colony-stimulating factor, the patient died 13 days after the diagnosis.     

Valvular heart disease in pregnancy. A contemporary perspective

Valvular heart disease may have a significant impact on the course and outcome of pregnancy with implications for fetal as well as maternal health. Optimally, serious symptomatic valvular heart disease should be detected and treated before pregnancy. Whether a pregnant woman is known to have valvular heart disease or is diagnosed during pregnancy, it is imperative that she is managed by an experienced multidisciplinary team. Although medical therapy may alleviate symptoms of heart failure in some patients, definitive intervention either with percutaneous balloon valvuloplasty or with surgical valve replacement may be necessary.