Respiratory, Cardiac, and Neuropsychiatric Manifestations of Postacute Sequelae of Coronavirus Disease 2019 in Lima, Peru.

Background: Few studies have examined the burden of postacute sequelae of coronavirus disease 2019 (COVID-19) (PASC) in low- and middle-income countries. We sought to characterize PASC with self-reported questionnaires and clinical examinations of end-organ function in Lima, Peru. Methods: From January to July 2021, we recruited participants at least 8 weeks after COVID-19 diagnosis from a case registry in Lima, Peru. We evaluated participants for PASC with questionnaires, neuropsychiatric evaluations, chest X-ray, spirometry, electrocardiogram, and echocardiogram. We used multivariable models to identify risk factors for PASC. Results: We assessed 989 participants for PASC at a median 4.7 months after diagnosis. Clinically significant respiratory symptoms were reported by 68.3% of participants, particularly those who had been severely ill during acute COVID-19, and were associated with cardiac findings of ventricular hypertrophy or dilation on echocardiogram. Neuropsychiatric questionnaires were consistent with depression in 20.7% and cognitive impairment in 8.0%. Female sex and older age were associated with increased risk of respiratory (adjusted odds ratio [aOR], 2.36 [95% confidence interval {CI}, 1.69-3.31] and aOR, 1.01 [95% CI, 1.00-1.03], respectively) and neuropsychiatric sequelae (aOR, 2.99 [95% CI, 2.16-4.18] and aOR, 1.02 [95% CI, 1.01-1.03], respectively). Conclusions: COVID-19 survivors in Lima, Peru, experienced frequent postacute respiratory symptoms and depression, particularly among older and female participants. Clinical examinations highlighted the need for cardiopulmonary rehabilitation among persons with severe COVID-19; psychosocial support may be required among all COVID-19 survivors.

Immunology of allergen immunotherapy.

Allergen immunotherapy (AIT) is the only disease-modifying therapy for allergic disease. Through repeated inoculations of low doses of allergen-either as whole proteins or peptides-patients can achieve a homeostatic balance between inflammatory effectors induced and/or associated with allergen contact, and mediators of immunologic non-responsiveness, potentially leading to sustained clinical improvements. AIT for airborne/respiratory tract allergens and insect venoms have traditionally been supplied subcutaneously, but other routes and modalities of administration can also be effective. Despite differences of allergen administration, there are some similarities of immunologic responses across platforms, with a general theme involving the restructuring and polarization of adaptive and innate immune effector cells. Here we review the immunology of AIT across various delivery platforms, including subcutaneous, sublingual, epicutaneous, intradermal, and intralymphatic approaches, emphasizing shared mechanisms associated with achieving immunologic non-responsiveness to allergen.

Anterior hybrid construction of multilevel cervical disc disease and spondylotic spinal stenosis: surgical results and factors affecting adjacent segment problems.

OBJECTIVE: We aimed to evaluate reliability, radiological outcomes, and the impacts of anterior cervical hybrid construction on the adjacent segments for the multilevel cervical degenerative disc disease (mCDDD) and spondylotic spinal stenosis (SSS). METHODS: A retrospective analysis was performed using data extracted from the medical files of 195 patients (105 males, 90 females; mean age: 47.7 years). From 2008 to 2018, these patients underwent anterior cervical hybrid construction for symptomatic contiguous at least 2-level cervical degenerative disc diseases and cervical spondylosis. Clinical and radiological data including Neck Disability Index (NDI), visual analogue scale (VAS), local cervical degenerative disk disease in adjacent segments on magnetic resonance imaging (MRI) views, and complications were reviewed. RESULTS: The mean clinical and radiological follow-up was 45.2 months (range 24 to 102). Radiculopathy and/or myelopathy were the main clinical problems in all patients. The mean VAS scores of HC for arm pain were 7.4 ± 0.8 preoperatively; 2.8 ± 0.6, 1 month after surgery; 2.3 ± 0.6, 6 months after surgery; 1.8 ± 0.6, 12 month after surgery; and 1.6 ± 0.6, 24 months after surgery. The mean NDI scores (mean ± SD) of HC significantly improved after surgery (on admission, 57.2 ± 5.5%; 1 month after surgery, 27.35 ± 5.3%; 6 month after surgery, 21.43 ± 2.8%; 12 months after surgery, 21.9 ± 2.3%; 24 months after surgery, 20.6 ± 2.6%, p = 0.006). Hoarseness and dysphagia were the most common complications and osteophyte formation was the most frequent radiographic change. CONCLUSION: Anterior cervical hybrid construction appears to be an acceptable option in the management of multilevel cervical degenerative disc diseases and spondylotic spinal stenosis.

Restructured Mitochondrial-Nuclear Interaction in Plasmodium falciparum Dormancy and Persister Survival after Artemisinin Exposure.

Artemisinin and its semisynthetic derivatives (ART) are fast acting, potent antimalarials; however, their use in malaria treatment is frequently confounded by recrudescences from bloodstream Plasmodium parasites that enter into and later reactivate from a dormant persister state. Here, we provide evidence that the mitochondria of dihydroartemisinin (DHA)-exposed persisters are dramatically altered and enlarged relative to the mitochondria of young, actively replicating ring forms. Restructured mitochondrial-nuclear associations and an altered metabolic state are consistent with stress from reactive oxygen species. New contacts between the mitochondria and nuclei may support communication pathways of mitochondrial retrograde signaling, resulting in transcriptional changes in the nucleus as a survival response. Further characterization of the organelle communication and metabolic dependencies of persisters may suggest strategies to combat recrudescences of malaria after treatment. IMPORTANCE The major first-line treatment for malaria, especially the deadliest form caused by Plasmodium falciparum, is combination therapy with an artemisinin-based drug (ART) plus a partner drug to assure complete cure. Without an effective partner drug, ART administration alone can fail because of the ability of small populations of blood-stage malaria parasites to enter into a dormant state and survive repeated treatments for a week or more. Understanding the nature of parasites in dormancy (persisters) and their ability to wake and reestablish actively propagating parasitemias (recrudesce) after ART exposure may suggest strategies to improve treatment outcomes and counter the threats posed by parasites that develop resistance to partner drugs. Here, we show that persisters have dramatically altered mitochondria and mitochondrial-nuclear interactions associated with features of metabolic quiescence. Restructured associations between the mitochondria and nuclei may support signaling pathways that enable the ART survival responses of dormancy.

Evidence for linkage of pfmdr1, pfcrt, and pfk13 polymorphisms to lumefantrine and mefloquine susceptibilities in a Plasmodium falciparum cross.

BACKGROUND: Lumefantrine and mefloquine are used worldwide in artemisinin-based combination therapy (ACT) of malaria. Better understanding of drug susceptibility and resistance is needed and can be obtained from studies of genetic crosses. METHODS: Drug response phenotypes of a cross between Plasmodium falciparum lines 803 (Cambodia) and GB4 (Ghana) were obtained as half-maximal effective concentrations (EC50s) and days to recovery (DTR) after 24 h exposure to 500 nM lumefantrine. EC50s of mefloquine, halofantrine, chloroquine, and dihydroartemisinin were also determined. Quantitative trait loci (QTL) analysis and statistical tests with candidate genes were used to identify polymorphisms associated with response phenotypes. RESULTS: Lumefantrine EC50s averaged 5.8-fold higher for the 803 than GB4 parent, and DTR results were 3-5 and 16-18 days, respectively. In 803 × GB4 progeny, outcomes of these two lumefantrine assays showed strong inverse correlation; these phenotypes also correlated strongly with mefloquine and halofantrine EC50s. By QTL analysis, lumefantrine and mefloquine phenotypes mapped to a chromosome 5 region containing codon polymorphisms N86Y and Y184F in the P. falciparum multidrug resistance 1 protein (PfMDR1). Statistical tests of candidate genes identified correlations between inheritance of PfK13 Kelch protein polymorphism C580Y (and possibly K189T) and lumefantrine and mefloquine susceptibilities. Correlations were detected between lumefantrine and chloroquine EC50s and polymorphisms N326S and I356T in the CVIET-type P. falciparum chloroquine resistance transporter (PfCRT) common to 803 and GB4. CONCLUSIONS: Correlations in this study suggest common mechanisms of action in lumefantrine, mefloquine, and halofantrine responses. PfK13 as well as PfMDR1 and PfCRT polymorphisms may affect access and/or action of these arylaminoalcohol drugs at locations of hemoglobin digestion and heme metabolism. In endemic regions, pressure from use of lumefantrine or mefloquine in ACTs may drive selection of PfK13 polymorphisms along with versions of PfMDR1 and PfCRT associated with lower susceptibility to these drugs.

Efficient Transmission of Mixed Plasmodium falciparum/vivax Infections From Humans to Mosquitoes.

BACKGROUND: In Southeast Asia, people are often coinfected with different species of malaria (Plasmodium falciparum [Pf] and Plasmodium vivax [Pv]) as well as with multiple clones of the same species. Whether particular species or clones within mixed infections are more readily transmitted to mosquitoes remains unknown. METHODS: Laboratory-reared Anopheles dirus were fed on blood from 119 Pf-infected Cambodian adults, with 5950 dissected to evaluate for transmitted infection. Among 12 persons who infected mosquitoes, polymerase chain reaction and amplicon deep sequencing were used to track species and clone-specific transmission to mosquitoes. RESULTS: Seven of 12 persons that infected mosquitoes harbored mixed Pf/Pv infection. Among these 7 persons, all transmitted Pv with 2 transmitting both Pf and Pv, leading to Pf/Pv coinfection in 21% of infected mosquitoes. Up to 4 clones of each species were detected within persons. Shifts in clone frequency were detected during transmission. However, in general, all parasite clones in humans were transmitted to mosquitoes, with individual mosquitoes frequently carrying multiple transmitted clones. CONCLUSIONS: Malaria diversity in human hosts was maintained in the parasite populations recovered from mosquitoes fed on their blood. However, in persons with mixed Pf/Pv malaria, Pv appears to be transmitted more readily, in association with more prevalent patent gametocytemia.

Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model.

Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance t1/2s (>5 h) and their association with mutations in Plasmodium falciparum Kelch-propeller protein K13. Here, we describe a P. falciparum laboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC50 measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.00; 95% CI, 0.62-1.61), whereas, in a ring-stage survival assay, the C580Y-type progeny had 19.6-fold (95% CI, 9.76-39.2) higher average counts. In splenectomized Aotus monkeys treated with three daily doses of i.v. artesunate, t1/2 calculations by three different methods yielded mean differences of 0.01 h (95% CI, -3.66 to 3.67), 0.80 h (95% CI, -0.92 to 2.53), and 2.07 h (95% CI, 0.77-3.36) between C580Y and C580 infections. Incidences of recrudescence were 57% in C580Y (4 of 7) versus 70% in C580 (7 of 10) infections (-13% difference; 95% CI, -58% to 35%). Allelic substitution of C580 in a C580Y-containing progeny clone (76H10) yielded a transformant (76H10C580Rev) that, in an infected monkey, recrudesced regularly 13 times over 500 d. Frequent recrudescences of ART-treated P. falciparum infections occur with or without K13 mutations and emphasize the need for improved partner drugs to effectively eliminate the parasites that persist through the ART component of combination therapy.

Kelch Mutations in Plasmodium falciparum Protein K13 Do Not Modulate Dormancy after Artemisinin Exposure and Sorbitol Selection In Vitro.

Some Kelch mutations of the Plasmodium falciparum K13 protein confer increased survival to dihydroartemisinin (DHA)-treated ring-stage parasites. Here, we asked if K13 mutations affect a dormancy phenotype allowing parasites to survive DHA exposure and then sorbitol selection. Although recrudescence from dormancy differed between two distinct parasite lines, it was similar for isogenic lines carrying single-site substitutions in K13. Therefore, K13 mutations do not alter the DHA-sorbitol combined dormancy phenotype; rather, traits from other loci likely determine this phenotype.

Implementing a collaborative sepsis protocol on the time to antibiotics in an emergency department of a saudi hospital: quasi randomized study.

Background. The objective of this study is to evaluate the impact of an ED sepsis protocol on the time to antibiotics for emergency department (ED) patients with severe sepsis. Methods. Quasiexperimental prospective study was conducted at the emergency department. Consecutive patients with severe sepsis were included before and after the implementation of a sepsis protocol. The outcome measures were time from recognition of severe sepsis/septic shock to first antibiotic dose delivery and the appropriateness of initial choice of antibiotics based on the presumed source of infection. Results. There were 47 patients in preintervention group and 112 patients in postintervention group. Before implementation, mean time from severe sepsis recognition to delivery of antibiotics was 140 ± 97 minutes. During the intervention period, the mean time was 68 ± 67 minutes, with an overall reduction of 72 minutes. The protocol resulted in an overall improvement of 37% in the compliance, as 62% received appropriate initial antibiotics for the presumed source of infection as compared to 25% before the start of protocol. Conclusion. Implementation of ED sepsis protocol improved the time from recognition of severe sepsis/septic shock to first antibiotic dose delivery as well as the appropriateness of initial antibiotic therapy.

Chronic obstructive pulmonary disease: hospital and intensive care unit outcomes in the Kingdom of Saudi Arabia.

BACKGROUND: There is little data surrounding the survival of patients with chronic obstructive pulmonary disease (COPD) who are admitted to the critical care unit with exacerbation of symptoms. We conducted a study to measure the in-hospital and intensive care unit (ICU) outcomes of patients admitted with COPD exacerbation, and identified the related prognostic factors. METHOD: We performed a retrospective cohort study of patients who were admitted to the adult ICU between January 2006 and July 2011 for COPD exacerbation in King Abdulaziz National Guard Hospital, Al-Hasa, Saudi Arabia. RESULTS: During the study period, a total of 119 patients were admitted to the ICU with acute respiratory failure attributed to COPD exacerbation. The mean age was 72 ± 13 years, and 44 (37%) were females. The main cause of respiratory failure was infection, which occurred in 102 (86%) patients. Thirty-nine (33%) of the admitted patients were mechanically ventilated, and the median duration was 2.6 (1-42) days. The median lengths of the ICU and hospital stays were 3 (1-40) and 9 (2-43) days, respectively. The ICU mortality was 6%, and hospital mortality was 11%. Low Glasgow Coma Scale on admission, intubation, duration of mechanical ventilation, current smoking, tracheostomy, cardiopulmonary arrest, and the development of acute renal failure were associated with higher hospital mortality. CONCLUSION: Early ICU and hospital mortality is low for COPD patients who have been admitted to the ICU with exacerbation. Low Glasgow Coma Scale scores on admission, intubation, prolonged use of mechanical ventilation, and the development of acute renal failure were identified as risk factors associated with increased hospital mortality.

Impact of 6-hour sepsis resuscitation bundle compliance on hospital mortality in a saudi hospital.

Purpose. To assess the effect of improved compliance with 6-hour sepsis resuscitation bundle on mortality in patients with severe sepsis and septic shock. Materials and Methods. A quasi-experimental prospective study was conducted at a 10-bedded combined medical and surgical intensive care unit. The historical group included all consecutive patients with severe sepsis and septic shock admitted from January 2008 to March 2009. Intervention included evidence-based written sepsis pathway, antibiotic recommendations, and an educational program.The post-intervention group included all consecutive patients admitted from July 2009 to June 2011. The primary outcome measures were the overall compliance to seven 6-hour sepsis resuscitation bundle elements and 30-day hospital mortality. There were 99 patients in the historical group and 199 in the post-intervention group. Results. The baseline patients' characteristics were similar. Overall compliance to all seven sepsis resuscitation bundle elements in historical group was 5.1% [95% confidence interval (CI), 2.1-11.3] which improved after intervention to 23.6% (95% CI, 17.9-30.1); P < 0.001. The overall compliance to 6-hour sepsis resuscitation bundle elements was associated with improved survival [odds ratio (OR), 5.8 (95% CI, 2.2-15.1; P < 0.001)]. 30-day hospital mortality reduced from 31.3% in the historical group to 21.1% in the intervention group; P = 0.05. Conclusion. Improvement in compliance to 6-hour sepsis resuscitation bundle was associated with a reduction in 30-day hospital mortality.

Venous thromboembolism risk and prophylaxis in a Saudi hospital.

OBJECTIVE: To evaluate the risk factors and physician's compliance to American College of Chest Physicians (ACCP) guidelines recommendations for venous thromboembolism (VTE) prevention at our hospital. METHODS: This retrospective cohort study was conducted at King Abdulaziz Hospital, Al-Ahsa, Saudi Arabia from November 2009 to December 2009. We used the American College of Chest Physicians (ACCP) 2008 guidelines and Caprini's scores to assess VTE risk and to determine whether patients had received recommended prophylaxis. All hospital in-patients aged 15 years or above were assessed for risk of VTE by reviewing the hospital chart. A data sheet was developed to obtain the data on demographics, VTE prophylaxis medication, dose, route, duration, and associated risk factors. The primary endpoint was the rate of appropriate thromboprophylaxis. RESULTS: Nine hundred and sixty-eight patients were included. The mean age was 40 +/- 18.7 years, and 647 (66.8%) were women. According to the ACCP criteria, 547 (56.5%) patients were at risk for VTE. Of 210 patients that qualified for prophylaxis, 117 (55.7%) received some form of prophylaxis. However, 46 (39.3%) of them received ACCP-recommended VTE prophylaxis. In contrast, 25.6% of patients with no risk, according to Caprini score, had thromboprophylaxis prescribed. CONCLUSION: This study demonstrates that only a small proportion of eligible patients received the recommended VTE prophylaxis. Efforts should be made to develop strategies to improve patient safety practices.

Pain management of children and adolescents with sickle cell disease presenting to the emergency department.

OBJECTIVE: To show and characterize our practice in the initial management of children and adolescents with sickle cell disease (SCD) presenting in acute painful crises, and to identify if there is a delay in patients getting the initial analgesics compared with standard guidelines. METHODS: This retrospective cohort study was conducted at the Emergency Department (ED) of King Abdulaziz Hospital, Al-Ahsa, Kingdom of Saudi Arabia. The study participants were patients who visited the ED with acute painful crises related to SCD between July 2006 and July 2007. Exclusion criteria included age younger than 5 years and those older than 18 years old. A structured medical records review was used to abstract the data. The data was then computed using the Statistical Package for Social Sciences (SPSS, Chicago, IL, USA) for Windows version 16. RESULTS: There were 270 patient visits made by 43 patients. The time to administration of initial analgesic drugs was 42.2 ± 20.4 minutes. Two hundred thirty-seven (87.7%) visits were discharged from ED after an average length of stay of 183.9 ± 129.3 minutes. The 3 most common initial analgesics used were morphine sulphate, voltaren, and paracetamol. The routes frequently used were intravenous, oral, and intramuscular. CONCLUSION: There was a delay in the administration of the initial analgesic and approximately a fifth of patients received their analgesics via an unrecommended intramuscular route.

Central venous catheter practice in an adult intensive care setting in the eastern province of Saudi Arabia.

OBJECTIVE: To study the standard central venous catheter (CVC) practice in an adult intensive care unit (ICU) for potential improvement. METHODS: This is a prospective descriptive study conducted in an adult ICU of the 300-bedded King Abdul- Aziz Hospital, Al-Ahsa, Saudi Arabia. All consecutive patients admitted over 18 months (April 2007 to September 2008) were included. Details of CVCs, indications, complications, and patients' demographic information were recorded daily until CVCs were removed. RESULTS: Overall, 379 patients had 474 CVCs, which accounted for 3024 catheter-days, with a mean duration of 6.35 +/- 4.7 days (95% confidence intervals: 5.92-6.78). The most common site of insertion was the internal jugular vein (230 [48.5%]); 192 (40.5%) subclavian catheters, and 52 (11%) femoral. The CVC utilization ratio was 0.64. The catheter related local infection (CRLI) rate was 4.6 per 1000 catheter-day (the highest in the femoral site) and the catheter-related bloodstream infection (CRBSI) rate was 1.98 per 1000 catheter-day (the highest for the jugular route). There were only a few mechanical complications including 2 pneumothoraces, 5 arterial cannulations, and a single significant catheter dislodgement causing respiratory failure. CONCLUSION: Our results suggest that the current CVC practice enabled us to keep the rate of complications low, which is comparable to international standards.

Pain practices in a Saudi emergency department.

OBJECTIVE: To describe analgesic practices among adults presenting to the emergency department (ED), and to determine factors affecting the timeliness and adequacy of analgesia. METHODS: A retrospective cohort study with descriptive and comparable data analysis was conducted on 2,199 patient visits. This included a structured medical records review for all adult patients (over 14 years old) from August 1, 2006 to October 31, 2006 that presented to the Emergency Department (ED) of King Abdul-Aziz Hospital, Al-Ahsa, Kingdom of Saudi Arabia. Patients with acute pain episode associated with sickle cell disease, headache, backache, renal colic, and trauma (specific isolated injuries) were included. Patients quantified their pain on arrival by using 2 scales. RESULTS: There were 2199 patient visits during the study period that included 1190 males (54.1%). The mean age was 24.4 10.6 years. One quarter of all the patients did not receive any analgesia in the ED. The median time to administration of initial analgesic was 54 minutes. Approximately one fourth of all patients were sent home with no analgesics. Data identified female patients and low triage level as the predictors for longer time to initial analgesia. CONCLUSION: Our data illustrate that adults with painful conditions in our ED often receive inadequate or no analgesic treatment.

Testing psychiatric stigma in a general hospital in Saudi Arabia.

OBJECTIVE: To measure the stigma of psychiatric illness in a general hospital setting, and to test the connection between common ideas people have of patients with psychiatric illness (personal responsibility, and dangerousness), and the generation of discriminatory behavior. METHODS: A cross-sectional survey through internal mail was carried out in all the hospital staff of King Abdulaziz Hospital in Al-Ahsa, Kingdom of Saudi Arabia. The questionnaire was distributed on the 1st of February, and the study was finished on the 12th of March 2008. The sample size of 860 staff members was included for the study. This study was approved by the Eastern Region National Guard's Health Affairs Research and Ethical Committee. RESULTS: Hospital staff had high scores (6.8/9) for caring attitude for patients with psychiatric illness. They had medium scores for fear (4/9), avoidance (4.8/9), and dangerousness (4.3/9). They had low scores (3.1/9) for anger feelings toward these patients. Discriminatory behavior was found to be the result of feeling that these patients are dangerous, but not because they were held responsible for their illness. CONCLUSION: Our staff had a caring attitude towards patients with psychiatric illness. The idea that the patients with psychiatric illness are to blame for their illness did not hold, while the idea that these patients are dangerous showed positive relationship with discriminatory behavior.

Extended spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae bacteremia. Risk factors and outcome in the eastern region of Saudi Arabia.

OBJECTIVE: To study the risk factors for bacteremia caused by Escherichia coli (E. coli) or Klebsiella pneumoniae (K. pneumoniae) producing extended-spectrum beta-lactamase (ESBL) and their outcome. METHODS: A case-control study was conducted in King Abdul-Aziz National Guard Hospital, Al-Ahsa, Kingdom of Saudi Arabia from January 2006 through December 2007. All adult patients for whom culture results were positive for E. coli or K. pneumoniae were eligible. Twenty-nine patients with ESBL producing bacteremia (cases) were compared with 80 patients with non-ESBL producing bacteremia controls. Hospital mortality was the primary end point. Univariable and multivariable logistic regression were performed to analyze risk factors for ESBL bacteremia and its 30-day mortality. RESULTS: A total of 109 patients with bacteremia were enrolled that included 29 cases and 80 controls. Forty-nine percent of the patients were male. The mean age was 60.2+/-21.1 years. Nosocomial infection was the only independent risk factor for bacteremia due to ESBL-producing pathogens (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.14-8.44, p=0.02). Overall 30-day mortality was 22%, and was similar in both groups. The nosocomial infection (OR 3.20, 95% CI 1.48-6.94, p=0.01), presentation with septic shock (OR 48.88, 95% CI 6.01-397.32, p=0.004), and intensive care unit care (OR 7.40, 95% CI 1.94 -28.34, p=0.001) were the independent risk factors for 30-day mortality. CONCLUSION: The ESBL rate is high in our study among the bacteremic patients. Nosocomial infection is identified both as a risk factor for ESBL bacteremia and mortality.

Quercetin sensitizes cells in a tumour-like low pH environment to hyperthermia.

Quercetin has been shown to act as a hyperthermia sensitizer by inhibiting the synthesis of heat shock protein 70 (HSP70) in a variety of tumour cell lines. It is most effective under conditions of low pH. This study was designed to test the hypothesis that quercetin suppresses thermotolerance development in cells adapted to growth at low pH and renders them as responsive as acutely acidified cells to hyperthermia-induced cytotoxicity. Chinese hamster ovarian carcinoma cells (OvCa) were exposed to 42 degrees C hyperthermia and/or quercetin (50-200 mm) at their growth pH of either 7.3 or 6.7 or after acute acidification from 7.3 to 6.7. Thermotolerance development was measured by colony survival. HSP70 synthesis and total protein synthesis were measured by radioactive precursor pulse labelling techniques. Quercetin, in a concentration-dependent manner, reduced the rate of total protein synthesis and increased cytotoxicity equally after acute acidification to pH 6.7 or growth at pH 6.7 at 37 degrees C, and to a greater extent than it did in cells at pH 7.3. At 42 degrees C, 100 mm quercetin inhibited total protein synthesis, HSP70 synthesis and thermotolerance development to a similar extent in cells grown at pH 6.7 or acutely acidified to pH 6.7. In contrast, quercetin reduced but did not completely inhibit HSP70 synthesis and thermotolerance development in cells grown and heated at pH 7.3. These results support the hypothesis that quercetin can specifically reduce thermotolerance development in tumour cells adapted to growth at pHe 6.7 so that they respond similarly to acutely acidified cells. Since many tumours are adapted to growth at low pH and may resist a wide variety of therapeutic modalities, inhibition of thermotolerance expression by quercetin may not only enhance the response to hyperthermia but the response to commonly used therapies such as chemotherapy and radiation.

Nonresponse to first-line pharmacotherapy may predict relapse and recurrence of remitted geriatric depression.

The authors examined whether nonresponse to first-line pharmacotherapy was associated with an increased probability of relapse or recurrence following remission of an episode of geriatric depression. The study group consisted of 74 elderly patients whose index episode of nonpsychotic unipolar major depression had responded to antidepressant pharmacotherapy. In 6 of these patients, the depressive episode had not responded to first-line pharmacotherapy (8 weeks of nortriptyline, including 2 weeks of adjunctive lithium) but it had responded to second-line treatment (phenelzine with or without adjunctive lithium). The 74 patients were maintained on acute doses of the medications that had led to response and were followed for 2 years or until relapse or recurrence, whichever occurred first. The cumulative probability of relapse or recurrence was 67% for patients who responded to second-line treatment compared with 18% for patients who responded to first-line treatment (P = 0.0003). As expected, mean time to response was significantly longer for patients who responded to second-line treatment but this factor did not account for the difference in outcome between the two groups. These findings suggest that pharmacotherapy resistance may constitute a risk factor for relapse or recurrence of remitted geriatric depression, even when patients are maintained on the medication that they eventually respond to.