Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors.

BACKGROUND: Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers. DESIGN: We conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III - IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute's Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism. RESULTS: Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0-1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26-312). CONCLUSIONS: Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration.

Influenza-like episodes in HIV-positive patients: the role of viral and 'atypical' infections.

OBJECTIVES: To document viral and 'atypical' infections in HIV-positive patients and association with influenza-like symptoms. PATIENTS AND METHODS: Monthly culture of urine, faeces and throat swabs in 63 HIV-positive patients (30 asymptomatic and 33 with AIDS-related complex/AIDS) over 5-27 months (with 1125 patient-months of follow-up), with further sample collections during influenza-like episodes. Standard viral detection methods were used. Throat swabs were assessed for Chlamydia sp. by culture and immunoblotting, and for Mycoplasma pneumoniae by polymerase chain reaction. RESULTS: Viruses were detected in 15 (50%) and M. pneumoniae in nine (30%) out of 30 HIV-positive patients during an influenza-like illness. A close temporal relationship with symptoms was observed in 12 (40%) patients: cytomegalovirus in six (20%), M. pneumoniae in three (10%), herpes simplex virus in three (10%), and enterovirus in one (4%). Influenza-like symptoms were more frequent in asymptomatic HIV infection than in AIDS-related complex/AIDS patients (actuarial risk at 1 year, 63 versus 26%; P=0.002), particularly in those with CD4 cell counts >300 x 10(6)/l at enrolment (P=0.002). At least 44% (four out of nine) M. pneumoniae infections were asymptomatic and 78% (seven out of nine) were associated with prolonged excretion (2-17 months). Chlamydia sp. were not detected. CONCLUSIONS: Influenza-like symptoms were more likely to be reported by HIV-positive patients at early stages of disease, possibly as a result of differences in immune responses to viral infection. There was a close association in 40% of cases between the development of symptoms and detection of cytomegalovirus, herpes simplex virus, enterovirus and M. pneumoniae (a previously unrecognized association).

Recurrent meningococcal septicaemia and properdin deficiency.

A 32-year-old male presented with two episodes of meningococcal septicaemia, each of which was caused by a different serogroup of Neisseria meningitidis. Examination of the alternative pathway of complement revealed the rare X-linked disorder properdin deficiency (PD). Meningococcal Infection in complement deficiency states is discussed and the unusual features of this case are highlighted.

Does isolation of patients with infections induce mental illness?

Forty-one patients admitted into single-bedded isolation cubicles in an infectious diseases unit were assessed for evidence of mental disturbance. By use of the Crown-Crisp Experimental Index as a measure of mental state, the scores for somatic anxiety, free floating anxiety, and the total score were found to be significantly raised on admission, falling towards those found in a control general practice population by the time of discharge from hospital. Higher scores were associated with a past history of mental illness. There was, however, no statistical correlation between the psychological indices and consumption of alcohol, smoking, or patient's sex. Clinically apparent behavioural disturbance, mainly anxiety and agitation, was seen in 12 patients. Overall, patients expressed a preference for single rooms and did not find the isolation rituals disconcerting. The findings indicate that anxiety in patients with acute infections is more related to their illness and referral to hospital than to their imposed isolation. Only those patients with a past psychiatric history are likely to benefit from transfer to an open ward during convalescence.

Epidemiology and molecular characterisation of toxigenic Corynebacterium diphtheriae var mitis from a case of cutaneous diphtheria in Manchester.

Diphtheria is now an uncommon disease in Britain. We describe an imported case of cutaneous diphtheria in a previously immunised adult cause by C. diphtheriae var mitis. The control measures adopted to deal with the index case and two secondary cases so as to limit further spread among household and school contacts are outlined. Molecular typing was used to study the mode of spread of the organism among contacts.

How useful is cerebrospinal fluid lactate estimation in differential diagnosis of meningitis?

Cerebrospinal fluid lactate (CSF) was measured by a rapid enzymatic method in 230 patients admitted with a suspected diagnosis of central nervous system infection. In all untreated cases of bacterial meningitis the levels exceeded 4.3 mmol/l and fell below 3.9 mmol/l in most patients with virus meningitis. We believe values of 3.9-4.3 mmol/l should be considered borderline as occasional CSF samples in cases of virus meningitis yield values in this range. However, distinction between untreated pyogenic meningitis and virus meningitis is rarely problematic in clinical practice, so routine use of the test as an emergency procedure offers no extra advantage. The test is unlikely to be of much help in differentiating partly treated bacterial meningitis from virus meningitis, but it is a valuable additional procedure for differentiating tuberculous meningitis from virus meningitis, highly modified bacterial meningitis and parameningeal septic states.

A double-masked, placebo-controlled trial of acyclovir cream in immunocompetent patients with herpes zoster.

Sixty-four patients with herpes zoster were entered into a randomised double-masked, placebo-controlled trial of 5% acyclovir cream applied five times daily for 5 days. Of these patients, 56 were included in the final analysis (26 acyclovir, 30 placebo). Significant and objective differences in either progression of the rash, severity of acute pain or incidence of post-herpetic neuralgia were not observed. Although significantly more rashes involuted in the acyclovir group, this isolated finding cannot be explained. Twenty-two patients (12 acyclovir, 10 placebo) experienced erythema or desquamation or both during treatment with the cream. The similar incidence of skin reactions in both groups suggests that they were related to the cream base rather than the acyclovir.

Once-weekly fluconazole to prevent recurrence of oropharyngeal candidiasis in patients with AIDS and AIDS-related complex: a double-blind placebo-controlled study.

Fluconazole 50 mg daily for 14-28 days was effective in the treatment of patients with AIDS and AIDS-related complex with severe oropharyngeal and oesophageal candidiasis. Of 24 patients entered, 17 (81%), including seven with oesophageal candidiasis, were clinically cured and two (9.5%) improved at the end of treatment. Following clinical cure, 14 patients were entered into the double-blind phase of the study, where fluconazole (150 mg) or placebo capsules were given once weekly. Treatment was double blind. Fluconazole 150 mg once weekly was found to be effective in maintaining patients both clinically and mycologically free of oropharyngeal candidiasis.

Crohn's disease with fistulae involving joints.

Two cases of Crohn's disease with unusual manifestations of fistulae involving joints are reported. One case with a fistula from the rectum through the pelvis presented with an abscess adjacent to the left hip joint. The second presented acutely with inflammation and swelling of the right thigh suggesting thrombophlebitis. This patient died from septicaemia and was found at postmortem to have ileal Crohn's disease with fistulae into the thigh, producing septic arthritis of the knee. The possibility of underlying Crohn's disease should be considered in patients who develop abscesses adjacent to the pelvis, or physical signs suggesting thrombophlebitis of the thigh.

Efficacy and effects on pulmonary function tests of weekly 600 mg aerosol pentamidine as prophylaxis against Pneumocystis carinii pneumonia.

A prospective study was designed to evaluate the efficacy and effects on pulmonary function tests of weekly 600 mg aerosolised pentamidine as prophylaxis against Pneumocystis carinii pneumonia (PCP) amongst two groups of patients infected with the human immunodeficiency virus. Group 1 (primary prophylaxis) consisted of patients with either diseases indicative of AIDS other than PCP or whose absolute CD4 positive lymphocyte count was below 200/mm3, and Group 2 (secondary prophylaxis) comprised patients with previous proven episodes of PCP. Fifty-five patients (30-Group 1, 25-Group 2) were studied over a period of 36 months, and no patients reached a study end point of either relapse or death due to PCP after a mean duration of treatment of 14.9 months (range 9-36 months). There were no significant differences between the pulmonary function tests (forced expiratory volume in the first second, forced vital capacity and carbon monoxide diffusion capacity) performed at the start and end of the study on both groups of surviving patients. Ten patients (18%) reported coughing and eight patients (15%) were documented to have bronchoconstriction, which was found to be preventable by prior administration of disodiumcromoglycate. The results showed that weekly 600 mg aerosolised pentamidine is effective and well tolerated for primary and secondary prophylaxis against PCP without additional adverse effects. Further prospective randomized trials are needed to determine whether doses higher than the current recommended 300 mg monthly dosage of aerosolised pentamidine provide more efficacy before such an alternative prophylactic treatment is generally adopted for patients who cannot tolerate other systemic agents.

Toxoplasmosis associated with digital vasculitis and immunodeficiency--a dilemma in diagnosis.

We present a case of acquired toxoplasmosis associated with severe digital vasculitis--a previously unreported finding. The rise in Toxoplasma gondii antibody titres may have been attenuated by impaired cellular immunity, and this poses a problem for diagnosis.

Successful late treatment of venous air embolism with hyperbaric oxygen.

A case of haemodialysis-associated venous air embolism is described. The patient commenced hyperbaric oxygen therapy 21 hours after the event when, despite appearing decerebrate, he made a complete recovery. This case underlines the importance of all clinicians being aware of those centres with facilities for hyperbaric therapy and the need to refer all patients with cerebral air embolism even following a prolonged delay.

The development of cytomegalovirus-induced adrenal failure in a patient with AIDS while receiving corticosteroid therapy.

We report a case of Addisonian crisis due to cytomegalovirus (CMV) adrenalitis occurring in a patient with AIDS while receiving supraphysiological doses of steroids for the treatment of Pneumocystis carinii pneumonia. The case highlights the importance of considering the diagnosis of adrenal failure in AIDS, even in patients receiving supraphysiological doses of steroids.

Double-blind placebo-controlled trial of erythromycin in the treatment of clinical campylobacter infection.

In a double-blind placebo-controlled trial in patients hospitalized with campylobacter infection, erythromycin lessened pain and curtailed the carriage state but otherwise did not alter the natural course of the illness, which proved to be a short-lived, self-limiting one, even in this selected group of hospitalized patients; the majority had become asymptomatic by the time of the bacteriological diagnosis. The rarity of bacteraemia is highlighted by the study.