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Gender differences in pain, fatigue, and depression in patients with cancer.

A quick review of virtually any research topic documents the pervasiveness of sex and gender bias throughout all of science. A large portion of both animal and human research has been, and continues to be, done primarily with male subjects. This gender bias influences research results and often leads to inappropriate and questionable generalizations of research findings, usually from studies done with male participants to females. Needless to say, this bias exists in symptom management research on pain, fatigue, and depression in patients with cancer. This article reviews the evidence from the studies on gender differences in pain, fatigue, and depression in patients with cancer. It should be noted that research studies on gender differences in cancer-related pain, fatigue, and depression are minimal in number, are restricted to studies of the differences in prevalence rates and severity scores, and for the most part have yielded inconsistent results. Additional investigations are warranted to determine whether the gender differences in prevalence rates and severity of these symptoms represent clinically meaningful differences. If these gender differences are substantiated, these findings will guide the design of studies to elucidate the underlying mechanisms for these differences, as well as the development and testing of gender specific interventions to treat cancer-related pain, fatigue, and depression.

Biomedical Research↗

An analysis of the effects of suicide prevention facilities on suicide rates in the United States.

Since the 1960s, there has been a massive effort to reduce suicide mortality in the United States through prevention centers which invite suicidal persons to phone for supportive services. In spite of virtually total lack of evidence concerning the efficacy of these services, they proliferated until, by 1973, nearly every metropolitan area in the United States had at least one. Suicide rates increased slightly throughout this time. We studied 1968 through 1973, the years of greatest growth of suicide prevention facilities, comparing suicide rates in counties that added these centers with counties that did not do so. An association of centers with the reduction of suicides in young white females emerged. This finding was replicated on a different set of counties for a different time span. The results are discussed in light of the fact that this group constitutes the major clients of these centers.

Adolescent↗

Prevention of upper respiratory tract infections by gargling: a randomized trial.

BACKGROUND: Gargling to wash the throat is commonly performed in Japan, and people believe that such hygienic routine, especially with gargle medicine, prevents upper respiratory tract infections (URTIs). Its effectiveness, however, has not been established by clinical trials. DESIGN: Randomized controlled trial carried out in 2002-2003 winter season and analyzed in 2003 and 2004. PARTICIPANTS: Healthy volunteers (387) aged 18 to 65 years. INTERVENTION: Participants were randomly assigned to water gargling, povidone-iodine gargling, and usual care (control). Subjects in the two gargling groups were requested to gargle with water or diluted povidone-iodine at least three times a day. Participants were followed for 60 days. MAIN OUTCOME MEASURES: The primary outcome measure was first URTI incidence. Severity of URTI symptoms among incident cases was also evaluated. Both outcomes were assessed with a self-administered symptom record. Analyses were performed on an intention-to-treat basis. RESULTS: A total of 130 participants contracted URTIs. The incidence rate of first URTI was 0.26 episodes/30 person-days among control subjects. The rate decreased to 0.17 episodes/30 person-days in the water gargling group, and 0.24 episodes/30 person-days in the povidone-iodine gargling group. Respective incidence rate ratios against controls were 0.64 (95% confidence interval [CI]=0.41-0.99) and 0.89 (95% CI=0.60-1.33). A Cox regression (proportional hazard model) revealed the efficacy of water gargling (hazard ratio=0.60, 95% CI=0.39-0.95). Even when a URTI occurred, water gargling tended to attenuate bronchial symptoms (p=0.055). CONCLUSIONS: Simple water gargling was effective to prevent URTIs among healthy people. This virtually cost-free modality would appreciably benefit the general population.

Adolescent↗

Apoptosis in lung injury and remodeling.

The mode of cell death termed apoptosis, sometimes referred to as programmed cell death, is as critical a determinant of cell population size as is cell proliferation. Although best characterized in cells of the immune system, apoptosis is now known to be a key factor in the maintenance of normal cell turnover within structural cells in the parenchyma of virtually every organ. Recent interest in apoptosis in the lung has sparked a surge of investigations designed to determine the roles of apoptosis in lung development, injury, and remodeling. Of particular recent interest are the roles of apoptosis in disease pathogenesis and resolution, in which the concept of apoptosis as a "programmed" cell death, i.e., genetically determined, is often more accurately viewed as "inappropriate cell suicide" with regard to its extent and/or timing. Data accumulating over the past decade have made clear the complexity of the control of lung cell apoptosis; concepts of the regulation of apoptosis originally determined in classical cell culture models are often, but not always, applicable to structural cells. For this reason, each of the many cell types of the lung must be studied as a potentially new subject with its own idiosyncrasies yet to be discovered. In light of the large volume of literature now available, this article focuses on the roles of apoptosis in three pathophysiological contexts: acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis. Each section presents key data describing the evidence for apoptosis in the lung, its possible relevance to disease pathogenesis, and proposed mechanisms that might suggest potential avenues for therapeutic intervention.

Animals↗

[Radiotherapy in multiple modality treatment of children with nephroblastoma].

The role of radiotherapy in multiple modality treatment of Wilms' tumor is evaluated in 225 children aged 3 months to 11.5 years (mean age 3.5 years) with stage III-IV. 184 (81.8%) patients presented with stage III, 93.7% with typical nephroblastoma. Intervention was combined with drug and radiotherapy in 99.6% patients. Exposure of the abdominal cavity in total focal doses of 10.5-50.2 Gy (mean dose 28 Gy) was carried out in 219 (97.3%) of 225 patients. Special attention is paid to the incidence of relapses, remote metastases, and survival of patients in relation to prognostic factors (sex, age, stage of tumor process, terms of exposure, and total focal doses). All patients were followed up for 2-203 months (median 32 months). During this period relapses and/or metastases were observed in 34.2% patients; 30.2% died because of disease progress. 35.1% children live without signs of disease for more than 5 years, 14.7% for more than 10 years. Relapses were more incident during the first year of treatment (in 65% children) and outside the exposed field (72.5% cases). 33.2% patients with stage III developed metastases after 1-49 months; the lungs were involved most often. Prolongation of the period between surgery and exposure of the abdominal cavity led to increase in the incidence of relapses in the abdominal cavity from 6.7% (up to 2 weeks) to 21.9% (more than 1 month), p = 0.02. Relapses were the most frequent in children aged over 4 years. This parameter virtually did not depend on the total focal dose. The absence of relationship between the incidence of local relapses and life span after exposure to a total focal dose of up to 21.6 Gy in comparison with higher doses recommends reduced doses for therapy without notable deterioration of the survival of patients with nephroblastoma.

Child↗

Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings.

OBJECTIVE: Methylphenidate (MPH), the most commonly prescribed drug for attention-deficit/hyperactivity disorder (ADHD), has a short half-life, which necessitates multiple daily doses. The need for multiple doses produces problems with medication administration during school and after-school hours, and therefore with compliance. Previous long-acting stimulants and preparations have shown effects equivalent to twice-daily dosing of MPH. This study tests the efficacy and duration of action, in natural and laboratory settings, of an extended-release MPH preparation designed to last 12 hours and therefore be equivalent to 3-times-daily dosing. METHODS: Sixty-eight children with ADHD, 6 to 12 years old, participated in a within-subject, double-blind comparison of placebo, immediate-release (IR) MPH 3 times a day (tid), and Concerta, a once-daily MPH formulation. Three dosing levels of medication were used: 5 mg IR MPH tid/18 mg Concerta once a day (qd); 10 mg IR MPH tid/36 mg Concerta qd; and 15 mg IR MPH tid/54 mg Concerta qd. All children were currently medicated with MPH at enrollment, and each child's dose level was based on that child's MPH dosing before the study. The doses of Concerta were selected to be comparable to the daily doses of MPH that each child received. To achieve the ascending rate of MPH delivery determined by initial investigations to provide the necessary continuous coverage, Concerta doses were 20% higher on a daily basis than a comparable tid regimen of IR MPH. Children received each medication condition for 7 days. The investigation was conducted in the context of a background clinical behavioral intervention in both the natural environment and the laboratory setting. Parents received behavioral parent training and teachers were taught to establish a school-home daily report card (DRC). A DRC is a list of individual target behaviors that represent a child's most salient areas of impairment. Teachers set daily goals for each child's impairment targets, and parents provided rewards at home for goal attainment. Each weekday, teachers completed the DRC, and it was used as a dependent measure of individualized medication response. Teachers and parents also completed weekly standardized ratings of behavior and treatment effectiveness. To evaluate the time course of medication effects, children spent 12 hours in a laboratory setting on Saturdays and medication effects were measured using procedures and methods adapted from our summer treatment program. Measures of classroom behavior and academic productivity/accuracy were taken in a laboratory classroom setting during which children completed independent math and reading worksheets. Measures of social behavior were taken in structured, small-group board game settings and unstructured recess settings. Measures included behavior frequency counts, academic problems completed and accuracy, independent observations, teacher and counselor ratings, and individualized behavioral target goals. Reports of adverse events, sleep quality, and appetite were collected. RESULTS: On virtually all measures in all settings, both drug conditions were significantly different from placebo, and the 2 drugs were not different from each other. In children's regular school settings, both medications improved behavior as measured by teacher ratings and individualized target behaviors (the DRC); these effects were seen into the evening as measured by parent ratings. In the laboratory setting, effects of Concerta were equivalent to tid MPH and lasted at least through 12 hours after dosing. Concerta was significantly superior to tid MPH on 2 parent rating scores, and when asked, more parents preferred Concerta than preferred tid IR MPH or placebo. Side effects on children's sleep and appetite were similar for the 2 preparations. In the lab setting, both medications improved productivity and accuracy on arithmetic seatwork assignments, disruptive and on-task behavior, and classroom rule following. Both medications improved children's rule following and negative behavior in small group board games, as well as in unstructured recess settings. Individual target behaviors also showed significant improvement with medication across domains in the laboratory setting. Children's behavior across settings deteriorated across the laboratory day, and the primary effect of medication was to prevent this deterioration as the day wore on. Results support the use of background behavioral treatment in clinical trials of stimulant medication, and illustrate the utility of a measure of individualized daily target goals (ie, the DRC) as an objective measure of medication response in both the laboratory and natural school settings. CONCLUSION: This investigation clearly supports the efficacy of the Concerta long-acting formulation of MPH for parents who desire to have medication benefits for their child throughout the day and early evening. (ABSTRACT TRUNCATED)

Analysis of Variance↗

Effectiveness of virtual reality for pediatric pain distraction during i.v. placement.

The objective of this study was to test the efficacy and suitability of virtual reality (VR) as a pain distraction for pediatric intravenous (i.v.) placement. Twenty children (12 boys, 8 girls) requiring i.v. placement for a magnetic resonance imaging/computed tomography (MRI/CT) scan were randomly assigned to two conditions: (1) VR distraction using Street Luge (5DT), presented via a head-mounted display, or (2) standard of care (topical anesthetic) with no distraction. Children, their parents, and nurses completed self-report questionnaires that assessed numerous health-related outcomes. Responses from the Faces Pain Scale-Revised indicated a fourfold increase in affective pain within the control condition; by contrast, no significant differences were detected within the VR condition. Significant associations between multiple measures of anticipatory anxiety, affective pain, i.v. pain intensity, and measures of past procedural pain provided support for the complex interplay of a multimodal assessment of pain perception. There was also a sufficient amount of evidence supporting the efficacy of Street Luge as a pediatric pain distraction tool during i.v. placement: an adequate level of presence, no simulator sickness, and significantly more child-, parent-, and nurse-reported satisfaction with pain management. VR pain distraction was positively endorsed by all reporters and is a promising tool for decreasing pain, and anxiety in children undergoing acute medical interventions. However, further research with larger sample sizes and other routine medical procedures is warranted.

Attention↗

Diagnosis and treatment of diabetic foot infections.

EXECUTIVE SUMMARY: 1. Foot infections in patients with diabetes cause substantial morbidity and frequent visits to health care professionals and may lead to amputation of a lower extremity. 2. Diabetic foot infections require attention to local (foot) and systemic (metabolic) issues and coordinated management, preferably by a multidisciplinary foot-care team (A-II). The team managing these infections should include, or have ready access to, an infectious diseases specialist or a medical microbiologist (B-II). 3. The major predisposing factor to these infections is foot ulceration, which is usually related to peripheral neuropathy. Peripheral vascular disease and various immunological disturbances play a secondary role. 4. Aerobic Gram-positive cocci (especially Staphylococcus aureus) are the predominant pathogens in diabetic foot infections. Patients who have chronic wounds or who have recently received antibiotic therapy may also be infected with Gram-negative rods, and those with foot ischemia or gangrene may have obligate anaerobic pathogens. 5. Wound infections must be diagnosed clinically on the basis of local (and occasionally systemic) signs and symptoms of inflammation. Laboratory (including microbiological) investigations are of limited use for diagnosing infection, except in cases of osteomyelitis (B-II). 6. Send appropriately obtained specimens for culture before starting empirical antibiotic therapy in all cases of infection, except perhaps those that are mild and previously untreated (B-III). Tissue specimens obtained by biopsy, ulcer curettage, or aspiration are preferable to wound swab specimens (A-I). 7. Imaging studies may help diagnose or better define deep, soft-tissue purulent collections and are usually needed to detect pathological findings in bone. Plain radiography may be adequate in many cases, but MRI (in preference to isotope scanning) is more sensitive and specific, especially for detection of soft-tissue lesions (A-I). 8. Infections should be categorized by their severity on the basis of readily assessable clinical and laboratory features (B-II). Most important among these are the specific tissues involved, the adequacy of arterial perfusion, and the presence of systemic toxicity or metabolic instability. Categorization helps determine the degree of risk to the patient and the limb and, thus, the urgency and venue of management. 9. Available evidence does not support treating clinically uninfected ulcers with antibiotic therapy (D-III). Antibiotic therapy is necessary for virtually all infected wounds, but it is often insufficient without appropriate wound care. 10. Select an empirical antibiotic regimen on the basis of the severity of the infection and the likely etiologic agent(s) (B-II). Therapy aimed solely at aerobic Gram-positive cocci may be sufficient for mild-to-moderate infections in patients who have not recently received antibiotic therapy (A-II). Broad-spectrum empirical therapy is not routinely required but is indicated for severe infections, pending culture results and antibiotic susceptibility data (B-III). Take into consideration any recent antibiotic therapy and local antibiotic susceptibility data, especially the prevalence of methicillin-resistant S. aureus (MRSA) or other resistant organisms. Definitive therapy should be based on both the culture results and susceptibility data and the clinical response to the empirical regimen (C-III). 11. There is only limited evidence with which to make informed choices among the various topical, oral, and parenteral antibiotic agents. Virtually all severe and some moderate infections require parenteral therapy, at least initially (C-III). Highly bioavailable oral antibiotics can be used in most mild and in many moderate infections, including some cases of osteomyelitis (A-II). Topical therapy may be used for some mild superficial infections (B-I). 12. Continue antibiotic therapy until there is evidence that the infection has resolved but not necessarily until a wound has healed. Suggestions for the duration of antibiotic therapy are as follows: for mild infections, 12 weeks usually suffices, but some require an additional 12 weeks; for moderate and severe infections, usually 24 weeks is sufficient, depending on the structures involved, the adequacy of debridement, the type of soft-tissue wound cover, and wound vascularity (A-II); and for osteomyelitis, generally at least 46 weeks is required, but a shorter duration is sufficient if the entire infected bone is removed, and probably a longer duration is needed if infected bone remains (B-II). 13. If an infection in a clinically stable patient fails to respond to 1 antibiotic courses, consider discontinuing all antimicrobials and, after a few days, obtaining optimal culture specimens (C-III). 14. Seek surgical consultation and, when needed, intervention for infections accompanied by a deep abscess, extensive bone or joint involvement, crepitus, substantial necrosis or gangrene, or necrotizing fasciitis (A-II). Evaluating the limb's arterial supply and revascularizing when indicated are particularly important. Surgeons with experience and interest in the field should be recruited by the foot-care team, if possible. 15. Providing optimal wound care, in addition to appropriate antibiotic treatment of the infection, is crucial for healing (A-I). This includes proper wound cleansing, debridement of any callus and necrotic tissue, and, especially, off-loading of pressure. There is insufficient evidence to recommend use of a specific wound dressing or any type of wound healing agents or products for infected foot wounds. 16. Patients with infected wounds require early and careful follow-up observation to ensure that the selected medical and surgical treatment regimens have been appropriate and effective (B-III). 17. Studies have not adequately defined the role of most adjunctive therapies for diabetic foot infections, but systematic reviews suggest that granulocyte colony-stimulating factors and systemic hyperbaric oxygen therapy may help prevent amputations (B-I). These treatments may be useful for severe infections or for those that have not adequately responded to therapy, despite correcting for all amenable local and systemic adverse factors. 18. Spread of infection to bone (osteitis or osteomyelitis) may be difficult to distinguish from noninfectious osteoarthropathy. Clinical examination and imaging tests may suffice, but bone biopsy is valuable for establishing the diagnosis of osteomyelitis, for defining the pathogenic organism(s), and for determining the antibiotic susceptibilities of such organisms (B-II). 19. Although this field has matured, further research is much needed. The committee especially recommends that adequately powered prospective studies be undertaken to elucidate and validate systems for classifying infection, diagnosing osteomyelitis, defining optimal antibiotic regimens in various situations, and clarifying the role of surgery in treating osteomyelitis (A-III).

Journal Article↗

The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism.

In western countries, Alzheimer's disease (AD) is the most common form of dementia. In fact, if left uncurbed, the economic cost of caring for AD patients could consume the entire gross national product of the USA by the middle of this century. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of both mild and moderate-to-severe Alzheimer's disease and possibly vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca2+ influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that memantine is thus well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including other forms of dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention.

Alzheimer Disease↗

Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer's disease and other neurologic disorders.

Alzheimer's disease (AD) is the most common form of dementia, as least in western countries. It has been estimated that the cost to society for caring for AD patients will consume the entire gross national product of the U.S.A. by the middle of this century if left unabated. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of moderate-to-severe Alzheimer's disease and possibly vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca(2+) influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that memantine is thus well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including other forms of dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention.

Alzheimer Disease↗

Effects of light deprivation on recovery from neglect and extinction induced by unilateral lesions of the medial agranular cortex and dorsocentral striatum.

A number of previous studies have indicated that an environmental manipulation, 48 h of light deprivation (LD), produces virtually complete and permanent behavioral recovery of function from neglect induced by medial agranular cortex (AGm) lesions. LD-induced behavioral recovery from neglect is correlated with physiological changes in the dorsolateral striatum, an area that contains the projection zone of AGm efferents in the dorsocentral striatum (DCS). In this study, the behavioral effects of 48 h of LD on subjects with either unilateral DCS, AGm, or combined AGm/DCS lesions were investigated to examine whether the integrity of the DCS is crucial for behavioral recovery from neglect and whether LD will have a therapeutic effect on extinction deficits. Subjects were tested for extinction to bilateral simultaneous stimulation of the forepaws, and visual, auditory and tactile neglect. Forty-eight hours of LD failed to produce behavioral recovery from neglect in rats with DCS lesions, or a therapeutic affect on extinction deficits in any of the groups. The results of this study further support the crucial role of the DCS in recovery from neglect induced by AGm lesions and suggests that the DCS may be the crucial site for the mechanisms leading to LD-induced recovery. Further, the ineffectiveness of LD on extinction suggests that components of the neglect syndrome are dissociable and may require different therapeutic interventions.

Animals↗

Apoptosis and cancer: strategies for integrating programmed cell death.

Virtually all human cells are endowed with the capacity to commit suicide using an evolutionarily conserved mechanism that involves activation of caspase-family cell death proteases. Caspase activation culminates in a cell death process known as "apoptosis." The activation of these intracellular proteases is carefully controlled through a delicate balance of anti- and pro-death proteins, serving to precisely regulate cell life span. Defects in the natural death pathway promote tumorigenesis by prolonging cell life span and hence cell accumulation. Low-grade B-cell malignancies, particularly follicular lymphoma and chronic lymphocytic leukemia (CLL) represent quintessential examples of human neoplasms characterized primarily by a problem with cell death rather than cell cycle. Because the cell suicide pathway is also required for tumor eradication by the immune system, anticancer drugs, and irradiation, cancer-associated defects in the cellular apoptosis machinery also play an important role in treatment failures. Monoclonal antibody-based therapies may provide opportunities to either bypass defects in apoptosis pathways or to activate latent apoptotic programs in cancer cells, particularly in lymphoid malignancies where tissue-specific antigens can be exploited for cell-selective activation of apoptosis. Recent knowledge about apoptosis pathways is reviewed, and some examples of opportunities for therapeutic intervention are discussed.

Animals↗

Child abuse: measuring a global problem.

Child abuse and neglect include four distinct conditions: physical abuse, neglect, emotional abuse and sexual abuse. The magnitude of the problem is not well defined. The lack of epidemiological data limits the extent to which sound public health and social welfare policies and intervention programmes could be developed, implemented and evaluated. In recent years two approaches have been developed to document the magnitude and nature of child abuse and neglect: regional or national case registers; and a screening instrument for suspected cases of child abuse and neglect (SCAN) for use in health service facilities. We are proposing an additional approach for monitoring presumed child abuse and neglect-related mortality. Applying this approach to regions or groups of countries for which there are sufficient data, the expected under-5 rate of presumed child abuse and neglect would be between 13 and 20 per 100,000 live births. These estimates are higher than those made either from community-based registers or forensic reporting systems. Differences in these estimates will need to be resolved through further research. Injury and injury-related mortality can be classified as intentional, unintentional or resulting from varying degrees of neglect. Death from physical abuse represents a willful act or series of actions. Death from neglect may arise from willful behaviour but may also arise from ignorance and irresponsible behaviour. These include failure to recognize hazardous circumstances or children's nutritional, health and developmental needs, and leaving infants and children unattended or inadequately supervised. Mortality data provide virtually no measure of sexual abuse.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group.

There are few blood pressure (BP) data reported for premature and term newborn infants after 24 hours of age. To determine BP levels and BP trends in a representative population of infants admitted to neonatal intensive care units (NICUs), this study was conducted in 14 NICUs in the greater Philadelphia area. All infants admitted to the 14 NICUs during a 3-month period were entered into the study. BP data, along with data on clinical conditions and therapeutic interventions (independent variables), were prospectively collected by a uniform protocol. Systolic BP (SBP) and diastolic BP (DBP) were measured indirectly by oscillometry and recorded every 8 hours. Data from 608 infants followed up for 1 to 99 days after delivery generated 9911 infant-day records and 24,052 individual BP measurements. On day 1, birth weight and gestational age were strong correlates of SBP (r = 0.68, p < 0.0001 and r = 0.66, p < 0.0001, respectively) and DBP (r = 0.48, p < 0.0001 and r = 0.47, p < 0.001, respectively). During the first 5 days of life there was a progressive rise in SBP (2.23 to 2.67 mm Hg/day) and DBP (1.58 to 2.02 mm Hg/day) regardless of gestational age or weight at birth. After day 5 there was a more gradual increment in the daily SBP (0.24 to 0.27 mm Hg/day) and DBP (0 to 0.15 mm Hg/day). Stepwise linear multiple regressions were used to examine the multiple correlations among the independent variables and to build a regression model for BP. Gestational age and day of life emerged in the first two steps of the multiple regression analysis (multiple R = 0.463 and 0.655, respectively; p < 0.0001 for both). The multiple R values for day of life and gestational age were virtually identical to that for postconceptional age (day of life + gestational age at birth). Although other common diagnosis and treatment variables contributed a small amount to the total variance in BP, postconceptional age was the primary determinant of BP in this population of infants.

Birth Weight↗

Effect of suprarenal stent struts on the renal artery with ostial calcification observed on CT virtual intravascular endoscopy.

OBJECTIVES: The behaviour of stent struts crossing the renal ostia and their effect on renal ostia configuration is not well understood. The study aims to investigate whether suprarenal stent struts affect the morphological change of the renal artery with ostial calcification observed on CT virtual intravascular endoscopy. METHODS: Nine patients with abdominal aortic aneurysms undergoing suprarenal fixation of stent grafts were included in the study. All patients received a Zenith endovascular graft with uncovered suprarenal components placed above the renal arteries. Renal ostial calcification and configuration of stent wires crossing the renal ostium were characterized in each patient and maximal transverse and longitudinal diameters of the renal ostia were measured on virtual endoscopy pre- and post-stent grafting. RESULTS: There were altogether 17 renal ostia assessed with one patient having atrophic left kidney and no renal ostium being observed. Ostial calcification was found in five of the left renal ostia and five of the right renal ostia with one patient having bilateral ostial calcification. There was no significant difference between the renal ostial diameters measured pre- and post-stent grafting (p>0.05). Suprarenal stent struts were found to cross the renal ostia in various configurations observed on virtual endoscopy. All of the renal arteries were patent on follow-up CT scans after suprarenal fixation without stenosis or occlusion being observed. One patient with atrophic left renal artery developed renal failure following suprarenal stent grafting and received renal dialysis, while in the remaining cases median serum creatinine level did not change significantly. CONCLUSIONS: Suprarenal stent struts did not significantly affect the renal ostia with ostial calcification in terms of the diameter measurements and renal function. Further studies deserve to investigate the long-term effect of stent struts on the renal artery in terms of cross-sectional area reduction caused by stent wires and ostial calcification.

Aged↗

Clinical outcomes resulting from telemedicine interventions: a systematic review.

BACKGROUND: The use of telemedicine is growing, but its efficacy for achieving comparable or improved clinical outcomes has not been established in many medical specialties. The objective of this systematic review was to evaluate the efficacy of telemedicine interventions for health outcomes in two classes of application: home-based and office/hospital-based. METHODS: Data sources for the study included deports of studies from the MEDLINE, EMBASE, CINAHL, and HealthSTAR databases; searching of bibliographies of review and other articles; and consultation of printed resources as well as investigators in the field. We included studies that were relevant to at least one of the two classes of telemedicine and addressed the assessment of efficacy for clinical outcomes with data of reported results. We excluded studies where the service did not historically require face-to-face encounters (e.g., radiology or pathology diagnosis). All included articles were abstracted and graded for quality and direction of the evidence. RESULTS: A total of 25 articles met inclusion criteria and were assessed. The strongest evidence for the efficacy of telemedicine in clinical outcomes comes from home-based telemedicine in the areas of chronic disease management, hypertension, and AIDS. The value of home glucose monitoring in diabetes mellitus is conflicting. There is also reasonable evidence that telemedicine is comparable to face-to-face care in emergency medicine and is beneficial in surgical and neonatal intensive care units as well as patient transfer in neurosurgery. CONCLUSIONS: Despite the widespread use of telemedicine in virtually all major areas of health care, evidence concerning the benefits of its use exists in only a small number of them. Further randomized controlled trials must be done to determine where its use is most effective.

Humans↗

Clinical equivalence of two cytokeratin markers in mon-small cell lung cancer: a study of tissue polypeptide antigen and cytokeratin 19 fragments.

STUDY OBJECTIVES: We have longstanding experience with tissue polypeptide antigen (TPA), a tumor marker of the cytokeratin (CK) family. In the mid-1990s, a new CK marker, CK 19 fragments (CYFRA 21-1), became popular and widely accepted. This is the first study specifically designed to compare the two markers. DESIGN: Analysis of a single institution database over a 3-year period (ie, 1998 to 2000). SETTING: Community-based hospital and second referral level institution for a province of 500,000 people. PATIENTS: The study included 180 new consecutive patients (143 men) with pathologically documented non-small cell lung cancer (NSCLC), who were observed during and after treatment, and eventually were assessed for status. INTERVENTIONS: Anthropometric, clinical, and laboratory data, including TPA and CYFRA 21-1 serum levels, were recorded prospectively. Standard nonparametric tests, Kaplan-Meyer survival analyses, Cox proportional hazards models, receiver-operating characteristic (ROC) curves, and estimates were used for statistical analysis. MEASUREMENTS AND RESULTS: A total of 1,299 twin TPA and CYFRA 21-1 serum assays (180 performed at diagnosis and 1,119 performed during or after treatment) were obtained. Intermarker correlation tests revealed incredibly high Spearman rho indexes, ranging from 0.935 at diagnosis to 0.813 to 0.921 at the different follow-up times. The substantial equivalence of the two tests explained all the other results, as follows: their similar profile of correlation with the other variables (objective treatment response: TPA rho, 0.456; CYFRA 21-1 rho, 0.463; follow-up performance status: rho range, 0.424 to 0.435); their superimposable capability to predict important clinical situations (eg, recognizing a metastatic disease at diagnosis with areas under the ROC curve of 0.742 and 0.706, respectively); their nearly identical prognostic significance (the D statistic of the goodness-of-fit of a multivariate survival model: TPA, 851.0; CYFRA 21-1, 851.6). CONCLUSIONS: In most of their traditional clinical applications the two serum tests are equivalent because of their virtual identity. We strongly recommend using a CK test in the evaluation of each NSCLC patient. The choice between TPA and CYFRA 21-1 can be based on nonclinical factors, such as the laboratory experience or preference, and the cost of the two kits.

Adult↗

Surrogate end-point biomarkers in chemopreventive drug development.

Relevant and feasible surrogate end-points are needed for the evaluation of intervention strategies against cancer and other chronic, life-threatening diseases. Carcinogenesis can be viewed as a process of progressive disorganization. This process is characterized by the accumulation of genotypic lesions and corresponding tissue and cellular abnormalities, including loss of proliferation and apoptosis controls. Potential surrogate end-points for cancer incidence include both phenotypic and genotypic biomarkers of this progression. In the US National Cancer Institute chemoprevention programme, histological modulation of a precancer (intraepithelial neoplasia) has so far been the primary phenotypic surrogate end-point in chemoprevention trials. Additionally, high priority has been given to biomarkers measuring specific and general genotypic changes correlated with the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at specific microsatellite loci). Other potential surrogate end-points include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers thought to be associated with cancer progression (e.g., prostate-specific antigen) are particularly appealing surrogate end-points because of accessibility. Potentially chemopreventive effects of the test agent may also be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). To establish chemopreventive efficacy, prevention of virtually all biomarker lesions, or of those lesions with particular propensity for progression, may be required. Ideally, the phenotype and genotype of any new or remaining precancers in the target tissue of chemopreventive agent-treated subjects would show less, and certainly no greater, potential for progression than those of placebo-treated subjects.

Anticarcinogenic Agents↗