In vitro chloroquine-resistant Plasmodium falciparum malaria in the Natal/Kwazulu area

Blood samples from 77 patients with Plasmodium falciparum malaria resident in the Natal/Kwazulu area, were tested for chloroquine resistance by an in vitro microtechnique; 6 of these patients were infected by asexual parasites which proved resistant in varying degrees to chloroquine. Resistance, expressed in terms of picomoles chloroquine base per well in which schizont development was completely inhibited, ranged from 16 pmol to greater than 24 pmol. On the evidence it would appear likely that these patients were infected during visits to Mozambique or areas immediately bordering Mozambique.     

In vivo and in vitro chloroquine-resistant falciparum malaria in Venda. A case report

A Venda child with Plasmodium falciparum malaria had a recurrence of illness 3 weeks after an adequate course of chloroquine. She was treated again with chloroquine and improved clinically but had persistent asexual parasitaemia during the 9 days after completion of the second course of treatment. At this stage chloroquine-resistant malaria was suspected but she was treated again with chloroquine in higher dosage, as alternative antimalarial drugs were not available locally. The patient recovered clinically, her parasitaemia cleared, and she showed no side-effects. Although not routinely recommended, a higher dose of chloroquine may be a useful option when alternative antimalarial drugs are not readily available. Chloroquine resistance was confirmed by Rieckmann's in vitro method, which showed complete inhibition of schizont development in the presence of 16 pmol chloroquine base per well instead of 6 pmol or less as seen with sensitive strains. This case is the first reported of proven chloroquine-resistant malaria acquired in the RSA. This single case does not indicate the existence of a drug-resistant malaria problem in the RSA but points to a need for clinical vigilance and for appropriate surveillance.     

Chloroquine-resistant Plasmodium falciparum malaria in the Kavango region of Namibia

The sensitivity to chloroquine of Plasmodium falciparum from the Kavango region of Namibia was determined by a 24-hour test in vitro. Twenty-six isolates were successfully tested, of which 11 were resistant to a low degree, schizogony being inhibited at 8 pmol/well. The results of the Dill-Glazko test for the presence of 4-aminoquinolines in urine indicate that chloroquine is not widely used in the area.     

In vitro confirmation of chloroquine-resistant Plasmodium falciparum malaria in KwaZulu

In May 1987 and January 1988 the chloroquine sensitivity of Plasmodium falciparum in the Ubombo and Ingwavuma districts of KwaZulu was determined by a modified in vitro microtest in which the patients' plasma was replaced with non-immune human AB serum and the test plates were incubated in an atmosphere of 3% oxygen, 4% carbon dioxide and 93% nitrogen. A success rate of 74% was achieved using this technique. All of 23 successfully tested isolates from malaria patients reporting to clinics and a hospital in these areas were found to be resistant to chloroquine, schizogony being inhibited at 32 pmol per well in the majority of tests. Seventy-five per cent of the isolates obtained through active surveillance in the Ubombo district were found to be resistant in varying degrees. Malarial parasites collected from clinics and a hospital in the endemic area did not change markedly in their in vitro response to chloroquine during the 8-month period May 1987-January 1988.     

Malaria at Johannesburg Hospital. A retrospective study

A total of 43 patients diagnosed as having malaria were admitted to Johannesburg Hospital during 1988; 40 (94%) were infected with Plasmodium falciparum. Only 26 patients (60%) were recorded as having used prophylaxis of any kind; chloroquine alone and in combination was used as prophylaxis by 17. Patients were treated with quinine (alone or in combination) in 67% of cases. In 42% of patients chloroquine-resistant malaria was considered a possibility.     

Cerebral cysticercosis. A case report and review of the literature

Despite the one-time hope that malaria would be eradicated, this disease is today still the world's most common severe parasitic disease involving man. The emergence of drug-resistant malaria, especially that due to Plasmodium falciparum, in 1961 therefore caused great concern, particularly among those seeking to control this scourge. Initially P. falciparum species were resistant to a varying degree to chloroquine. Subsequently chloroquine resistance has been followed by resistance to almost all antimalarial agents to which the organism has been exposed by man. Guidance in the diagnosis and treatment of chloroquine-resistant malaria is outlined, as well as the difficulties involved. Further problems which accompany pregnancy complicated by drug-resistant malaria are briefly mentioned. Ways of approaching and possibly retarding the development of drug-resistant malaria are discussed.     

Plasmodium vivax: therapy update

IMPACT OF PLASMODIUM VIVAX WORLDWIDE: Plasmodium vivax is the most widespread malanal agent in the world. Unlike Plasmodium falciparum, P. vivax can cause early or late recurrence and is not fatal (benign tertian malaria). EMERGENCE OF RESISTANT STRAINS: P. vivax strains resistant to chloroquine, then primaquine, have emerged over the last decade, creating the need for a new therapeutic strategy. TREATMENT OF PRIMARY DISEASE: Generally, chloroquine is the first intention treatment, excepting patients who also have P. falciparum infection or a strain with suspected resistance to chloroquine. Mefloquine, quinine and halofantrine are also logical alternatives. TREATMENT OF RECURRENT DISEASE: A schizonticidal agent should be given followed by a hypnozoitocidal agent, primaquine. Primaquine dosage should now be raised or adjusted to the patient's weight. THERAPEUTIC PERSPECTIVES: Tafenoquine, delayed-release amino-8-quinoleine, is a potential alternative for primaquine for the treatment of recurrences. Studies are also in progress to evaluate the role of primaquine as a prophylaxic agent.     

Regulation of PTH1 receptor expression by uremic ultrafiltrate in UMR 106-01 osteoblast-like cells

BACKGROUND: Homologous down-regulation/desensitization of the parathyroid hormone receptor (PTH1R)/adenylate cyclase system has been demonstrated in uremia, and may contribute to parathyroid hormone (PTH) resistance; however, additional studies have shown that parathyroidectomy fails to normalize the down-regulation of the PTH1R. The present studies were designed to test directly, in vitro, the hypothesis that factors circulating in the uremic environment, other than PTH, decrease the response of osteoblastic cells to PTH. METHODS: Studies were conducted in confluent cultures of UMR 106-01 osteoblast-like cells. Uremic ultrafiltrate (UUF) was obtained from patients on hemodialysis. Cells were exposed to media containing 50% uremic ultrafiltrate for periods of up to 72 hours. Control cultures were exposed to a buffered salt solution containing a comparable ionic composition to that of the UUF. PTH-stimulated cyclic adenosine monophosphate (cAMP) generation was determined by radioimmunoassay (RIA), PTH binding and PTH1R mRNA levels were determined by radioligand binding and Northern analysis, respectively. RESULTS: PTH-stimulated cAMP generation from cultures treated with uremic ultrafiltrate for 48 hours was 1385.8 +/- 183.2 pmol/culture/5 minutes, whereas control cultures generated 2389.5 +/- 271 pmol cAMP/culture/5 minutes (P < 0.05). PTH binding was decreased by 30% in cultures incubated with UUF as compared to controls. The decrease in binding induced by UUF was accompanied by a decrease in PTH1R mRNA levels. CONCLUSION: These findings demonstrate that factors present in UUF decrease PTH-stimulated cAMP generation by a mechanism that involves a decrease in the levels of PTH1R mRNA levels. Thus, the skeletal resistance to PTH in the setting of chronic kidney disease, may be explained, at least in part, by circulating factors other than PTH.     

Continuous peritoneal dialysis in acute renal failure from severe falciparum malaria

Severe falciparum malaria complicated by acute renal failure resulted in very high mortality. Ten patients with acute renal failure from falciparum malaria (infected rbc up to 80%) were continuously dialysed using Tenckhoff peritoneal catheter. Five were oliguric and BUN was maintained between 60 to 80 mg/dl (21.4 to 28.6 mmol/l) by hourly 1 to 1.5 liter dialysate exchange during the acute phase. The peritoneal urea clearance (mean +/- SD) was 12.1 +/- 1.2 ml/min with urea nitrogen removal of 13.4 +/- 2.3 g/day. In nonoliguric cases dialysis was also needed for additional removal of waste products since the remaining renal function could not cope with the hypercatabolic state. Peritoneal glucose absorption (135 to 565 g/day) gave considerable caloric supply without volume load and also contributed to the prevention of hypoglycemia. Varying degree of acute respiratory failure developed in all patients with 5 cases (2 oliguric and 3 nonoliguric) progressing to pulmonary edema. Swan-Ganz catheterization and hemodynamic study suggested the role of increased capillary permeability and volume overload from endogenous water formation in the development of pulmonary complication. Continuous removal of fluid and waste products minimized these problems and may prevent the progression of respiratory failure. One patient died of severe sepsis and the other nine survived. This study showed the beneficial contribution of continuous peritoneal dialysis in the management of acute renal failure from severe falciparum malaria.     

Chloroquine resistance in Plasmodium falciparum in KwaZulu, 1983-1988

Patients with Plasmodium falciparum infections in northern KwaZulu adjacent to the Mozambique border were treated with chloroquine 25 mg/kg. Persistent parasitaemias increased from nil in 1983 to 21.2% and 16.1% for hospital and field treatments respectively in 1987. After a change to sulfadoxine-pyrimethamine (Fansidar; Roche) treatment (adults 1,500 mg and 75 mg respectively) these rates fell in March 1988 to 6.9% and 0.4%.     

Efficacy of primary wound cultures in long bone open extremity fractures: are they of any value?

The management of long bone open extremity fractures has included initial wound cultures, antibiotics, operative debridement, and fracture repair, if indicated. The value of initial wound cultures is unclear. We examined whether primary wound cultures predict which wounds will become infected, and whether bacterial growth on primary wound cultures correlates with bacteria cultured from infected wounds. This prospective study involved patients presenting to a regional trauma center. Before any interventions were performed, initial aerobic and anaerobic cultures of the wounds of 117 consecutive open extremity fractures grades I-III were obtained. The results of these cultures were correlated with the development of a wound infection, and if an infection occurred, the organism grown from the infected wound was compared with any organism grown from the primary wound cultures. Of the initial cultures, 76% (89/117) did not demonstrate any growth, while the other 24% (28/117) only grew skin flora. There were only 7 (6%) wound infections, and 71% (5/7) initially did not grow any organisms. Of the isolates that grew from the initial cultures, none were the organisms that eventually led to wound infections. The use of primary wound cultures in open extremity injuries has no value in the management of patients suffering long bone open extremity fractures.     

Chloroquine-resistant malaria. A case report

Chloroquine-resistant Plasmodium falciparum malaria contracted in Mozambique by a patient taking correct prophylaxis is reported. The fact that misdiagnosis of malaria still occurs, the need to have intravenous quinine readily available country-wide, and the fact that a P. falciparum strain resistant to chloroquine is present across our border are stressed.     

Routine drainage in cholecystectomy. A bacteriologic and clinical assessment.

A prospective study was carried out to determine the possible role of exogenous and endogenous bacteria in the development of postoperative complications in patients in whom drainage was routinely employed after cholecystectomy. In 100 patients undergoing cholecystectomy because of cholelithiasis, cultures were made of specimens taken from the bile during operation and from the drains. Bile cultures were positive in thirty-eight patients. Drain cultures were positive in thirty-five patients, with most of the bacteria cultured being from an exogenous source (in most cases staphylococcus). The rate of postoperative complications was found to be significantly higher in the group with positive bile cultures (of endogenous origin) than in the group with positive drain cultures (of exogenous origin) or sterile cultures. In the patients with positive bile cultures, the rate of wound infection was 31 per cent, whereas in those with positive drain cultures it was 5.7 per cent, and in those with sterile drains only 4 per cent. These findings indicate that if the bile is not infected, the risk of wound infection is considerably reduced and that the bacteria of exogenous source do not play a prominent role in the development of postoperative complications. In consideration of this as well as the fact that the use of a drain may obviate the need for reexploration in patients in whom there is postoperative leakage of bile or blood, routine drainage should not be rejected categorically in “clean” abdominal operations.     

Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme

BACKGROUND: Results of the current therapy for GBM are dismal; the mean survival time of patients is approximately 1 year-and it has been so for several decades. In preliminary studies, we have observed a potentiating therapeutic effect when chloroquine was added to the conventional treatment of GBM. METHODS: Over the last 5 years, 41 patients with GBM received chloroquine as an optional adjuvant administered concurrently with conventional surgery, chemotherapy, and radiotherapy. These patients did not participate in our previous studies on chloroquine administration and were studied retrospectively; 82 contemporary patients with GBM who did not receive chloroquine were included in this analysis as control subjects. The end point observed was time of survival after surgery. RESULTS: Survival time in patients treated with chloroquine was 25 +/- 3.4 months, as compared with that of 11.4 +/- 1.3 months in control subjects (P = .000; OR = 0.4; 95% CI = 0.26-0.6); the difference remained significant after regression analysis for possible clinical confounders. CONCLUSIONS: In agreement with our recent reports, chloroquine exerts a strong adjuvant effect when added to the conventional treatment of GBM. In this large cohort of unselected patients with GBM who were treated with chloroquine, the median survival time doubled as compared with that of control subjects.     

Blackwater fever

DEFINITION: Blackwater fever is a clinical entity characterized by acute intravascular hemolysis classically occuring after the re-introduction of quinine in long-term residents in Plasmodium falciparum endemic areas and repeatedly using the product. CLINICAL PROFILE: The symptomatology appears brutally with emission of porto-colored urine, icterus, pallor, nausea, fever and acute renal failure. The hemolytic-like anemia is immediately severe. Parasitemia is mild or absent. The mechanism of renal failure is tubular necrosis. QUININE AND SIMILAR MOLECULES: Well known at the start of the 20th century, blackwater fever has become exceptional since 1950, when quinine was replaced by chloroquine. The disease reappeared in 1990, following the re-utilization of quinine because of resistance to chloroquine. Thereafter, several cases have been described with halofantrine and mefloquine, two new molecules similar to quinine (amino-alcohol family). The physiopathogenesis of the disease is not well known, however it would appear that the concomitance of a double sensitivization of the red blood cells to the P. falciparum red blood cells and to the amino-alcohols is necessary to provoke the hemolysis. EVOLUTION: The severity of the clinical picture often requires initial management in intensive care unit. Nowadays, however, prognosis is good and the disease usually regresses without after effects.     

Testosterone metabolism in primary cultures of epithelial cells and stroma from benign prostatic hyperplasia

We studied the metabolism of testosterone in primary cultures of prostate epithelial cells and fibroblasts obtained from patients with benign prostatic hyperplasia (BPH). The conversion of ³H-testosterone in both cell cultures was predominantly to the oxidative pathway, with the formation of ³H-androstenedione increasing with cell number and time of incubation. Although we also detected some 5-reductase activity in these cells, the activity in the stroma component (0.00688 pmol/mg protein/min) was nonetheless insignificant when compared to the 5-reductase activity in the tissue of origin (0.0616 pmol/mg protein/min) and well below the 17-hydroxysteroid dehydrogenase activity of the same cells (0.0518 pmol/mg protein/min). The aromatase activity in our cells was also measured by two separate techniques, but neither the deuterium procedure nor the production of oestrone from androgen precursors yielded any positive results, suggesting that under these experimental conditions there was no aromatase activity within the cells. The shift from the reductive to the oxidative pathways in these primary cell cultures was reminiscent of the androgen-metabolizing enzyme profiles seen in poorly differentiated prostate cancer. Whether this fransition is an obligatory step in the development of hormone refractiveness remains to be elucidated.     

Chloroquine-resistant Plasmodium falciparum malaria in South Africa. A case report

Chloroquine-resistant plasmodium falciparum malaria has been described in many parts of the world, including Africa as far south as south-western Africa. We report a case of chloroquine-resistant P. falciparum cerebral malaria in the RSA. It seems likely that the infection was acquired in the Louis Trichardt district of the northern Transvaal. Despite the administration of an adequate course of chloroquine, the parasitaemia failed to clear and even increased (type III resistance). Eventually clinical and laboratory-proven cure was obtained only after combined quinine and tetracycline therapy. To our knowledge this is the first case of chloroquine-resistant P. falciparum malaria acquired in the RSA.     

Alpha-Defensin Offers Limited Utility in Routine Workup of Periprosthetic Joint Infection

BackgroundAlpha-defensin (AD) is a synovial biomarker included as a minor criterion in the scoring system for diagnosing periprosthetic joint infection (PJI). The purpose of this study is to study the impact of AD on diagnosis and management of PJI.MethodsSynovial fluid from 522 patients after total knee and hip arthroplasty was retrospective reviewed. Synovial white blood cell count, percentage of neutrophils, and culture from the AD immunoassay laboratory were reviewed with serum erythrocyte sedimentation rate and C-reactive protein values from our institution. A modified version of the 2018 scoring system for diagnosis of PJI was used, only scoring white blood cell count, percentage of neutrophils, erythrocyte sedimentation rate, and C-reactive protein. AD was then analyzed with these scores to determine if AD changed diagnostic findings or clinical management.ResultsEight-two patients were categorized as “infected” (score ≥6), of which 76 patients had positive AD. Of the 6 “infected” patients with negative AD, 2 had positive cultures (Staphylococcus epidermidis). Two-hundred thirteen patients were diagnosed as “possibly infected” (score 2-5). Fourteen of these patients had positive AD, of which 5 had positive cultures assisting with the diagnosis. The AD test changed the diagnosis from “possibly infected” to “infected” in 8 patients (1.5%) but only altered treatment plan in 6 patients (1.1%). A score <2 (not infected) was calculated in 227 patients with no patients having positive AD.ConclusionAD may be beneficial in some cases where laboratory values are otherwise equivocal; however, its routine use for the diagnosis of PJI may not be warranted.     

Reactivation of latent murine cytomegalovirus from kidney

Cytomegalovirus (CMV) is presumed to cause latent infection, but the sites of infection are incompletely known. We propose that latent murine cytomegalovirus is present in kidney and may be reactivated by explanation. Immunosuppressive agents and allogeneic stimuli may enhance this process. Balb/c mice were infected 11 to 14 months previously with 10(5) pfu of Smith strain murine cytomegalovirus intraperitoneally. Kidneys from 15 infected and nine uninfected mice were washed, minced into 1 to 2 mm2 explants and placed into separate tissue culture wells containing a mouse embryo fibroblast monolayer. Explants were untreated or treated with azathioprine, cyclophosphamide, anti-thymocyte serum, or allogeneic lymphocytes. Daily observations for CPE and passage of supernatant to fresh mouse embryo fibroblast were done. Standard cultures of blood, kidney, and salivary gland were negative. However, virus was isolated from the explants of 8/15 animals, with a reactivation time of 30 to 70 days. No significant difference in reactivation time was noted between treated or untreated explants. Restriction enzyme analysis of viral DNA confirmed identity with the original strain. These data show that latent murine cytomegalovirus is present in murine kidney tissue and may be reactivated by explantation.     

Effect of bombesin on plasma cholecystokinin in normal persons and gastrectomized patients measured by sequence-specific radioimmunoassays

Since bombesin is known to stimulate pancreatic enzyme secretion and gallbladder contraction, we have measured plasma cholecystokinin (CCK) concentrations during bombesin infusion using sequence-specific radioimmunoassays. Antibody 1703 binds to COOH terminal CCK peptides containing at least 14 amino acid residues, while antibody T204 is specific for the sulfated tyrosine region of CCK. In nine normal persons infusion of increasing doses of bombesin (2.4, 6, 18, and 60 pmol/kg X 20 min) induced dose-related integrated plasma CCK responses (58.5 +/- 9.7, 70.5 +/- 12.2, 79.5 +/- 11.1, and 101.4 +/- 15.4 pmol/L X 20 min [antibody 1703] and 50.4 +/- 11.9, 62.0 +/- 13.4, 74.7 +/- 9.2, and 116.1 +/- 11.3 pmol/L X 20 min [antibody T204]). Infusion of 60 pmol bombesin/kg X 20 min in eight patients with partial gastrectomy resulted in similar increases in plasma CCK (8.1 +/- 1.8 pmol/L, antibody 1703; 9.5 +/- 2.0 pmol/L, antibody T204) as in eight normal control subjects (6.5 +/- 0.9 pmol/L, antibody 1703; 8.8 +/- 1.0 pmol/L, antibody T204). During infusion of bombesin, plasma gastrin levels increased from 16.7 +/- 1.4 to 49.6 +/- 8.1 pmol/L (P less than 0.005) in the normal persons, while there was no significant change in plasma gastrin levels in gastrectomized patients. Bombesin did not significantly influence gastric acid secretion in three patients with partial gastrectomy studied. It is concluded that infusion of bombesin releases CCK in humans by a gastrin-independent mechanism.