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PubMed2003

Diabetes gene therapy: potential and challenges.

Gene therapy, developing rapidly as a result of advances in molecular biology and the Human Genome Project, is now highlighted as a most hopeful technology of the 21st century. The major goal of gene therapy in diabetes mellitus (DM) is to maintain euglycemia in face of wide variations in dietary intake. Although some obstacles remain to be overcome, the risk-benefit ratio of gene therapy in DM is better than that of lifelong injections of insulin, and islet transplantation, which faces the problems of donor shortage and rejection. This review focuses on the recent advances in gene therapy of insulin-requiring diabetes, with particular emphasis on 1. the gene delivery systems by viral vectors, since most gene therapy approaches for DM involve the use of viral vectors, paying special attention to current efforts to overcome the disadvantages of adenovirus, adenovirus-associated virus and retrovirus vectors and targeting gene delivery for optimal efficiency of gene expression; 2. coupling the synthesis and release of the transgene insulin to serum glucose concentrations, especially with reference to the current promoters controlling at transcriptional level the ectopic insulin expression in autologous hepatocytes; 3. beta-cell replacement strategies: engineering of beta-cells, especially those derived from pluripotent stem cells, non beta-cells, and on a new comer, the K cells. Recent advances in the use of stem cells for potential application in diabetes gene therapy are also discussed.

Adenoviridae↗
PubMedDate not supplied

[Neurocysticercosis].

INTRODUCTION: This paper review current literature about neurocysticercosis with emphasis on recent advances on diagnosis and therapy. DEVELOPMENT: Cysticercosis is the most common parasitic disease of the nervous system. The disease occurs when humans become the intermediate host in the life cycle of Taenia solium by ingesting its eggs from contaminated food. Endemic in developing countries of Latin America, Asia and Africa, massive immigration of people to industrialized nations caused a recent increase in the number of patients with cysticercosis in the United States of America and in some European countries. Neurocysticercosis is a pleomorphic disease due to individual differences in the number, size, and location of the parasites within the nervous system as well as to differences in the severity of the host's immune reaction against the parasite. Epilepsy, focal neurological signs, and intracranial hypertension are the most common clinical manifestations of neurocysticercosis. Since the diagnosis is not possible on clinical grounds, it is necessary the practice of complementary exams in every suspected case. Neuroimaging studies (CT or MRI) usually permit the diagnosis as they show objective evidence of the parasites and the inflammatory changes induced in the surrounding nervous tissue. Immunological tests developed to detect anticysticercal antibodies in serum or CSF present many problems inherent to the lack of specificity or sensibility; therefore, they should not be used by themselves to confirm or exclude the disease. Two drugs, albendazole and praziquantel, have been used with success to destroy most intracranial parasites; however, surgery still play a role in the management of some forms of the disease, particularly hydrocephalus and intraventricular cysts. CONCLUSIONS: Development of modern diagnostic tests and introduction of potent cestocidal drugs have increased our knowledge on neurocysticercosis and have improved its prognosis. Nevertheless, some patients still have torpid clinical courses despite proper therapy.

Africa↗
PubMed2006

[Hopes for gene therapy for cardiac failure].

Although the drug therapies developed over the last decades have improved the prognosis of congestive cardiac failure, the condition remains a principal cause of mortality and hospital admission in the industrialised world. The hopes for gene therapy in cardiac failure are based on the possibility of acting on the underlying physiopathological mechanisms by the transfer of genetic material to the failing myocardium. A number of experimental studies targeting the regulation of the calcium ATPase of the sarcoplasmic reticulum, the pathways of beta-adrenergic desensibilisation and the pathways of apoptosis reported encouraging results. Although improvements in the efficacy and safety of techniques of vector construction and methods of delivery to the myocardium incite a certain optimism, the clinical benefits of gene therapy in cardiac failure have yet to be demonstrated.

Apoptosis↗
PubMed2003

Charcoal-based hemodiabsorption liver support for episodic type C hepatic encephalopathy.

OBJECTIVES: Episodic (acute) type C hepatic encephalopathy (AHE) fails to respond to 5 days of medical therapy in 10-30% of patients and carries a 10-30% mortality rate. We prospectively studied extracorporeal liver support for AHE failing to respond to medical therapy to assess its safety and efficacy and the role of anticoagulation. METHODS: A series of patients with cirrhosis and AHE failing to respond to at least 24 h of medical therapy underwent a maximum of three 6-h charcoal-based hemodiabsorption (Liver Dialysis Unit) treatments. A standard anticoagulation protocol, with heparin dosing based on activated clotting time (ACT) determinations, heparin dose-response curve, and target ACT of 275-300 s, was developed. Therapy was terminated if patients met a predetermined clinical response, deteriorated, or underwent transplantation. RESULTS: Eighteen patients with grade 2-4 AHE despite 5.9 +/- 3.9 days of medical therapy underwent a mean of 1.6 treatments. In 2.6 +/- 1.9 days, 16 patients (88.9%) improved to less than grade 2 HE or achieved at least a 50% hepatic encephalopathy index (HEI) reduction. Median mental status (grade 2 vs 1, p < 0.05) and HEI (0.634 +/- 0.194 vs 0.363 +/- 0.263, p < 0.005) improved significantly. Survival was 94.4% and 72.2% at 5 and 30 days, respectively. Use of our developed anticoagulation protocol resulted in less platelet (14.2% +/- 2.8% vs 32.5% +/- 5.8%, p < 0.005) and fibrinogen consumption (12.1% +/- 3.5% vs 43.3% +/- 8.6%, p < 0.0005) and blood product use (6.2 +/- 1.8 vs 19.0 +/- 5.6 units, p < 0.05) compared with treatments according to manufacturer's guidelines. CONCLUSIONS: Charcoal-based hemodiabsorption treatments in which a standardized anticoagulation protocol is used is safe and effective treatment for AHE not responding to standard medical therapy.

Adult↗
PubMed2006

Costimulatory molecules as targets for the induction of transplantation tolerance.

Transplantation is the only cure for end-stage organ failure. Transplanted tissues are usually recognized by the immune system as foreign and are rapidly rejected in the absence of immunosuppression. Transplanted organs between genetically distinct individuals are termed allografts and their acute rejection is orchestrated by the activation of allospecific T cells. To prevent acute allograft rejection, current therapies suppress all T cells irrespective of their specificities and must be taken life-long, leaving patients with decreased defenses against infectious agents and cancers. The goal in transplantation research is to develop therapies with the capacity to induce graft-specific tolerance. Ideal therapies should be of short duration and target only alloreactive T cells, leaving other T cells competent to fight infections and cancers. Researchers have studied the mechanisms of activation/regulation of T cells in the hopes that manipulation of these pathways may facilitate the induction of tolerance. Activation of T cells requires recognition by the T cell receptor (TCR) of antigenic peptides presented within major histocompatibility complexes (MHC) on the surface of antigen-presenting cells (APCs). In addition, concurrent engagement of costimulatory receptors on T cells by ligands on APCs is also required for optimal T cell responses, such that the ultimate outcome of TCR engagement reflects the relative sum of multiple positive and negative costimulatory signals. Targeting costimulatory receptor/ligand pairs has been used effectively to induce allograft tolerance in specific rodent transplantation models. This strategy has however been less effective in larger mammals. In this review, we will summarize the different reagents used to target costimulatory molecules, their effects, and the possible reasons limiting their efficacy in higher order mammals.

Animals↗
PubMed1983

Posterior subcapsular cataracts, associated with long-term corticosteroid therapy. Prednisolone versus 6 alpha-fluor-16 alpha-methyl-1-dehydrocorticosterone.

The side effects of corticosteroid therapy were studied in 50 children on long-term therapy for nephrotic syndrome or various collagen diseases. The treatment consisted of prednisolone given to 24 children, and Ultralan (6 alpha-fluor-16 alpha-methyl-1-dehydrocorticosterone) given to 15 patients, both in an alternate-day fashion. Both drugs as well as methylprednisolone and dexamethasone were given successively to 11 children. Duration of therapy and doses were equivalent in all patients studied. The patients on Ultralan therapy developed posterior subcapsular cataracts to a significant higher degree (10 out of 15) and more rapidly (after a cumulative dose of 5.0-10.0 g/m2 body surface area on 1-2 years duration of therapy) than on prednisolone monotherapy or on mixed steroid therapy.

Adolescent↗
PubMed1981

Nephrotic syndrome associated with lithium therapy.

Two patients on long-term lithium therapy developed the nephrotic syndrome. Ultrastructural study of a renal biopsy in each case showed extensive glomerular epithelial cell foot process fusion. Lithium was withdrawn in each case. The nephrotic syndrome cleared without steroid therapy and has not recurred 18 months later in one patient. The other patient required a further course of treatment with lithium and the nephrotic syndrome returned. Further biopsy revealed a more severe glomerular lesion. The nephrotic syndrome responded again to withdrawal of lithium and institution of steroid therapy. Lithium is known to cause acute renal failure and tubulo-interstitial disease, but the recently described association with proteinuria or nephrotic syndrome is little recognized.

Adult↗
PubMed1993

[A case of myasthenia gravis associated with multiple sclerosis and positive anticardiolipin antibodies].

A 42-year-old housewife with myasthenia gravis (MG) for 22 years, who was initially treated by radiation to the hyperplastic thymus and anti-cholinesterase therapy, developed bilateral ptosis, paresthesia of her right face and decreased taste sensation after house work at the age of 42 years. Neurological examinations revealed lateral and vertical gaze palsy, upward nystagmus, decreased taste sensation, peripheral facial palsy on the left side. She also had hypalgesia on the right face, arm and chest up to Th7 level, and urinary retention. She had hyperreflexia on the right side but no extensor toe signs. CSF study revealed 5 cells/microliters and protein of 23 mg/dl. Serum IgG anticardiolipin antibody was positive. Magnetic resonance imaging studies revealed high intensity areas in the brainstem tegmentum and periventricular white matter. Diagnosis of multiple sclerosis (MS) was made. This is the first case in which MG, MS and serum anticardiolipin antibody were present simultaneously, which may be all due to some immunological abnormality. Steroid therapy made anti-cardiolipin antibody negative, but new MS plaque developed in 7 months, which favors diagnosis of MS rather than infarction, since the activities of ACLA were not correlating to clinical symptoms. MRI was helpful in detecting MS plaques in MG patients.

Adult↗
PubMed1987

Intraocular and extraocular retinoblastoma.

Retinoblastoma, the most common primary ocular malignancy of childhood, is a tumor in which the pediatrician and pediatric oncologist can now play a much more significant role in therapy. Developments in molecular biology have now made carrier testing and prenatal diagnosis feasible. In the near future, these developments should greatly augment the pediatrician's and pediatric oncologist's ability to offer accurate and appropriate genetic counseling for affected families. A practical staging system for extraocular retinoblastoma together with stage-related effective chemotherapy and radiation therapy was presented in this chapter. These modalities now make possible long-term survival for the majority of the 1 out of 8 children with retinoblastoma who would otherwise die from metastatic disease. Finally, 40 per cent of all children with retinoblastoma (those with the germinal mutation) are at lifelong risk for second, nonocular malignancies. The recognition that more than half of these children will actually develop second tumors by the fourth decade of life makes vigilant follow-up care for these patients a necessity.

Bone Neoplasms↗
PubMed2005

Factors associated with sensorineural hearing loss among survivors of extracorporeal membrane oxygenation therapy.

OBJECTIVES: To endeavor to explain why some graduates of extracorporeal membrane oxygenation (ECMO) therapy develop sensorineural hearing loss (SNHL) whereas others do not, to study the variability seen in the degree of SNHL, to attempt to explain why some graduates with SNHL experience progressive worsening whereas others do not, and to describe the time course of the onset of SNHL on the basis of identified risk factors. DESIGN: A retrospective chart review with proportional-hazards regression analysis to identify specific risk factors for SNHL from a list of patient and treatment variables. SETTING: Children's Hospital Boston, a pediatric tertiary-care facility and ECMO center. PATIENTS: Neonatal ECMO graduates born in 1986-1994 who survived to discharge and underwent audiologic evaluations (n = 111) and a random sample of ECMO graduates who survived to discharge and did not undergo audiologic evaluations (n = 30). OUTCOME MEASURES: Audiologic data, including the presence or absence of SNHL, the severity of SNHL at the most recent evaluation, the stability or progressive worsening of hearing (with the first evaluation compared with the most recent evaluation), and the occurrence of delayed-onset SNHL. RESULTS: Twenty-nine (26%) of 111 ECMO graduates who underwent audiologic testing had SNHL at the last evaluation. Of these 29 subjects with SNHL, 21 (72%) had progressive SNHL, of whom 14 (48%) had delayed-onset SNHL. The age of identification of SNHL ranged from 4 months to 8 years 11 months. Factors identified with proportional-hazards regression analyses as being associated significantly with the time to onset of SNHL were a primary diagnosis of congenital diaphragmatic hernia (hazard ratio: 2.60), length of ECMO therapy (hazard ratio: 7.18), and number of days children received aminoglycoside antibiotics (hazard ratio: 5.56). Kaplan-Meier "time-to-event" curves were constructed to illustrate the time course of onset of SNHL, as affected by each of the variables identified as significant risk factors. CONCLUSIONS: These findings illustrate the need for early, routine, audiologic evaluations throughout childhood for all ECMO graduates. Children at even greater risk for developing SNHL because of a history of congenital diaphragmatic hernia, prolonged ECMO therapy, and/or a lengthy course of aminoglycoside antibiotic therapy should be monitored even more closely throughout childhood, depending on the child's individual risk indicators, as suggested here. On the basis of these risk indicators, efforts can be made to minimize the risk of hearing loss while a child is being treated with ECMO. In addition, these risk indicators can assist with counseling families of ECMO graduates regarding the child's specific risk of developing SNHL and how it can be managed should it occur.

Aminoglycosides↗
PubMed1994

[Problems of radiotherapy in Germany after the recent events in Hamburg].

BACKGROUND: During the 3rd Symposium on "Experimental Radiotherapy and Clinical Radiobiology" (Hamburg, March 1994) the consequences of the recent events in the Department of Radiotherapy of the University-Hospital in Hamburg for daily radiotherapy practice in Germany were discussed. The following topics were covered: information of the patient, choice of therapy, development of new treatment modalities, ethics committee, follow-up and role of radiobiology. DISCUSSION AND RESULTS: Information of the patient: Due to the insecure juridical situation in Germany there is a tendency to inform patients excessively, which is rather confusing for them. Adequate information of patients is a difficult task for physicians considering their daily workload. Choice of therapy: Unfortunately in Germany radiotherapists are often not initially involved in planning of the overall treatment strategy for individual cancer patients. The recent events in Hamburg led to a decreased referral of cancer patients for radiotherapy. This might even hold for tumor entities where radiotherapy is an essential part of therapy. Another problem is that dose might be reduced inadequately. This would reduce complications but also significantly increase local failure. Development of new treatment modalities: There are no special juridical problems with the conduction of clinical studies for optimization of radiation treatments. Ethics committee: Ethics committees are not only meant to safeguard patients but also protect physicians and institutions from the consequences of questionable research. FOLLOW-UP: Only radio-oncologists are adequately trained for follow-up after radiation treatment. Nevertheless, because of administrative, financial, legal and political problems many patients in Germany are not regularly seen by the radiation oncologist after end of radiation treatment. Always when new treatment strategies are established, careful follow-up is of special concern. Role of radiobiology: The main obligation of clinical radiobiology is to introduce radiobiological knowledge into clinical practice. This may be best promoted by a period of radiobiological research during residency. However, close collaboration between radiotherapists and radiobiologists is only possible at very few centres in Germany, because the institutes of radiobiology are dismantled systemically.

Aftercare↗
PubMed1978

Dream phenomena induced by chronic levodopa therapy.

Twenty-seven of eighty-eight (30.7%) Parkinsonian patients on chronic levodopa or levodopa/carbidopa therapy developed drug related dream phenomena. The patients reported three separate types of new dreams which we have classified as vivid dreams, night terrors and nightmares. These dreams are correlated to the duration of levodopa therapy although the mechanism of their production is unclear.

Adult↗
PubMed1985

[Invasive pulmonary aspergillosis--a diagnostic and therapeutic problem in patients with severe aplastic anemia].

Three young patients with severe aplastic anemia undergoing intensive immunosuppressive therapy developed fever and pulmonary infiltrates during longlasting severe granulocytopenia, despite multiple broad spectrum antibiotic combinations and granulocyte transfusions. Invasive pulmonary aspergillosis was diagnosed only by thoracotomy. In conjunction with high dose amphotericin-B therapy complete resolution of aspergillosis was achieved in two cases, paralleled by slow recovery of bone marrow function, whereas in the third case only a partial remission was possible together with transient amelioration of granulopoiesis. We suggest early aggressive surgical methods to establish the diagnosis of aspergillosis in these severely menaced patients, so that antifungal therapy with high dose amphotericin-B can be initiated at an early stage.

Adolescent↗
PubMed1991

Chronic motor cortex stimulation for the treatment of central pain.

Twelve patients with deafferentation pain secondary to central nervous system lesions were subjected to chronic motor cortex stimulation. The motor cortex was mapped as carefully as possible and the electrode was placed in the region where muscle twitch of painful area can be observed with the lowest threshold. 5 of the 12 patients reported complete absence of previous pain with intermittent stimulation at 1 year following the initiation of this therapy. Improvements in hemiparesis was also observed in most of these patients. The pain of these patients was typically barbiturate-sensitive and morphine-resistant. Another 3 patients had some degree of residual pain but considerable reduction of pain was still obtained by stimulation. Thus, 8 of the 12 patients (67%) had continued effect of this therapy after 1 year. In 3 patients, revisions of the electrode placement were needed because stimulation became incapable of inducing muscle twitch even with higher stimulation intensity. The effect of stimulation on pain and capability of producing muscle twitch disappeared simultaneously in these cases and the effect reappeared after the revisions, indicating that appropriate stimulation of the motor cortex is definitely necessary for obtaining satisfactory pain control in these patients. None of the patients subjected to this therapy developed neither observable nor electroencephalographic seizure activity.

Adult↗
PubMed1996

Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria.

1. The aim of this study was to assess the pharmacokinetics, clinical efficacy and safety of artemisinin alone and in combination with mefloquine. 2. Thirty-eight adults with symptomatic Plasmodium falciparum malaria were randomly assigned to receive either artemisinin (500 mg single dose followed by another 500 mg on day 1 and then 250 mg twice daily for 4 days) or artemisinin (500 mg single dose followed by 750 mg on day 1 and then 250 mg three times daily for one more day) in co-administration with mefloquine (250 mg three times daily for the first day). All drug administration was by the oral route. Patients were hospitalized at the Kibaha Designated District Hospital, Kibaha, Tanzania, for 6 days and a follow up for 3 weeks was performed. 3. Treatment with the artemisinin/mefloquine combination resulted in a shorter parasite clearance time (PCT) of 24 (22, 27; 95% confidence interval) h vs 31 (27, 36) h and fever subsidence time (FST) of 14 (12, 16) h vs 20 (18, 23) h compared with artemisinin monotherapy. The 95% CI for the difference of the PCT and FST were 1.7, 12 and 3, 10, respectively. Parasites were detected in 7 out of 17 patients (41%) receiving artemisinin monotherapy at the 3rd and 4th week follow up visits. No parasites were detected after the combination therapy. 4. The maximum plasma concentrations (Cmax) were similar after artemisinin monotherapy (615.4 +/- 387.0 ng ml-1) and in combination with mefloquine (851.8 +/- 523.6 ng ml-1). Elimination half-lives (t1/2) were also identical at 2.2 +/- 0.6 h and 2.5 +/- 0.7 h, respectively. However, the AUC values were higher (P < 0.05) after combination therapy (3252 +/- 1873 ng ml-1 h) than after monotherapy (2234 +/- 1502 ng ml-1 h). The oral clearance values were lower (P < 0.05) after combination therapy (195.4 +/- 86.9 l h-1) than after monotherapy (314.3 +/- 189.4 l h-1). PCT and FST normalized to initial parasitaemia correlated with AUC(0, t) (rs = 0.56, P = 0.02, rs = 0.58, P = 0.01, respectively) and with Cmax (rs = 0.62, P = 0.01, rs = 0.68, P = 0.005, respectively) in the artemisinin monotherapy only. 5. One patient on the combination therapy developed a psychiatric condition and two patients on the monotherapy developed skin itch.

Administration, Oral↗
PubMed2004

[Sarcoidosis granuloma on a tattoo induced by interferon alpha].

BACKGROUND: The side effects attributed to interferon alpha are numerous, including autoimmune events such as lupus, arthritis or thyroiditis. Emergence of sarcoidosis in patients with interferon alpha therapy is much more rare. We describe a case occurring in a patient treated for melanoma. CASE REPORT: A 54 Year-old woman who had been treated for fifty Months with low dose interferon alpha (Roféron(R), 3 millions units, three times a week) for a melanoma of the scalp (adjuvant therapy), developed labial nodules on a permanent tattoo. The diagnosis of sarcoid granuloma was confirmed by histopathologic analysis. Physical examination revealed dyspnea on exertion with a moderate pulmonary interstitial infiltrate on the CT Scan. The diagnosis of cutaneous and pulmonary sarcoidosis in association with interferon alpha therapy was made. Within 4 weeks, skin nodules began to regress although interferon was pursued at the same dose. Four Months later, at the end of interferon therapy, the nodules had totally disappeared. DISCUSSION: About forty cases of cutaneous or systemic sarcoidosis in patients treated with interferon alpha have been reported, but none of these cases concerned patients treated for melanoma. Interferon alpha might promote the development of sarcoid granuloma by inducing a switch of cytokine secretion from a Th2 to a Th1 cytokine pattern. It is very important to recognize cutaneous sarcoidosis during interferon alpha treatment because pulmonary sarcoidosis can be confused with common general side effects observed with such treatment.

Antineoplastic Agents↗
PubMed2001

Medical therapy or coronary artery bypass graft surgery for chronic stable angina: an update using decision analysis.

PURPOSE: Randomized trials comparing medical and surgical therapies for the treatment of chronic stable angina were completed in the early 1980s. Therapies developed since then have decreased mortality and myocardial infarction rates from coronary artery disease. Using decision analysis and incorporating current recommendations for treatment, we simulated a trial comparing coronary artery bypass graft surgery and medical therapy. METHODS: A Markov decision analysis model was constructed to compare the 5-year and 10-year outcomes of a simulated trial of medical therapy versus bypass surgery for stable chronic angina. Baseline data were obtained from a meta-analysis of trials comparing the two treatments. Data on risk reduction from contemporary therapies were obtained from randomized trials and meta-analyses. RESULTS: All subgroups experienced modest gains in survival with current therapies. At 5 years, the survival rate was 90% in the medical group (an absolute gain of 6%) and 94% in the surgical group (an absolute gain of 4%). Similar results were obtained for patients with triple-vessel disease. Among patients with a low ejection fraction, the 5-year survival rate was 85% for medical patients and 92% for surgical patients. Sensitivity analyses did not substantially affect the conclusions. CONCLUSION: Advances in the treatment of chronic stable angina have improved the outcome both for patients treated initially with surgery and for those treated initially with medical therapy. The improvements were of similar magnitude in both groups, so the fundamental conclusions of the bypass trials are unchanged.

Adult↗
PubMedDate not supplied

[Central nervous system mycotic infections].

INTRODUCTION: There has been an increased number of cases of fungal diseases of the central nervous system (CNS) during the past few years. This paper reviews current literature about these conditions, with emphasis on recent advances on diagnosis and therapy. DEVELOPMENT: While some fungi may cause disease in normal hosts, most of these microorganisms are opportunistics and affect immunocompromised hosts. With the exception of Candida albicans, that is a normal inhabitant of the intestinal tract, most fungi enter the body by inhalation or through skin abrasions. Common fungal diseases include aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, paracoccidioidomycosis, and phaeohyphomycosis. In general terms, fungal invasion of the CNS may produce one or more of the following clinical syndromes: subacute or chronic meningitis, encephalitis, parenchymal brain abscesses or granulomas, stroke, or myelopathy. Diagnosis may be difficult on clinical grounds, and data provided by neuroimaging studies or CSF examination is non-specific. Definitive diagnosis usually rest on the demonstration of the causal agent on body fluids or tissue samples. Early administration of amphotericin B, associated or not with the new azoles, is indicated to arrest the often fatal course of these conditions. CONCLUSIONS: Formerly considered rare diseases, the acquired immunodeficiency syndrome (AIDS) epidemic and the widespread use of corticosteroids and cytotoxic agents, have caused an increase in the prevalence of CNS mycosis. Development of potent antimycotic drugs have improved the prognosis of fungal diseases of the CNS. However, due to diagnostic delays or the presence of debilitating conditions, some patients still have torpid clinical courses despite proper therapy.

Central Nervous System Fungal Infections↗