Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase

We have previously reported that greater than 60% of human leukemic T- cell lines possess mutations in the p53 tumor suppressor gene. To determine whether T-cell acute lymphoblastic leukemia (T-ALL) patient samples possess p53 mutations, we screened peripheral blood-and bone marrow-derived leukemia samples, taken at diagnosis and at relapse, for p53 mutations. Exons 4 through 9 and selected intron regions of the p53 gene were analyzed using polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. p53 mutations were found in 0 of 15 T-ALL diagnosis samples, as compared with 10 of 36 (28%) T-ALL relapse samples. To determine whether p53 mutations play a role in the recurrence (relapse) of T-ALL, two special groups of T-ALL patients were studied: (1) a group of 8 relapse patients whose disease was refractory to chemotherapeutic treatment, and (2) a group of 6 "paired" T-ALL cell samples from patients for whom we possess both diagnosis and relapse samples. Three of 8 relapsed patients (37.5%) whose disease was refractory to the reinduction of remission by chemotherapy possessed missense mutations of the p53 gene. All 3 cases had mutations in exon 5. Among the paired samples, 3 of 6 patients harbored p53 mutations at disease recurrence, but possessed only wild- type p53 alleles at diagnosis. One case had mutation on exon 4, 1 case in exon 5, and 1 case in exon 8 with loss of heterozygosity. These data clearly indicate that recurrence of T-ALL is associated with missense mutations in p53. Our results indicate that (1) mutations of p53 do occur in T-ALL in vivo, and such mutations are associated with the relapse phase of the disease; and (2) p53 mutation is involved in the progression of T-ALL. This conclusion is supported by our observation that the introduction of T-ALL-derived mutant p53 expression constructs into T-ALL cell lines further increases their growth rate in culture, enhances cell cloning in methylcellulose, and increases tumor formation in nude mice.     

Long-term follow-up of consequences of percutaneous endoscopic gastrostomy (PEG) tubes in nursing home patients

PEG (percutaneous endoscopic gastrostomy) tubes are frequently placed in nursing home patients. The aim of this study was to assess retrospectively the long-term changes in functional and nutritional statuses, tube-related complications, and factors influencing survival in 46 nursing home residents, mean age 73.6 years (range 19–96). Functional status was evaluated by a standard rehabilitation medicine scale. Nutritional status was evaluated by serum albumin and cholesterol concentrations and by weight. PEG-related complications requiring hospitalization or emergency room or clinic evaluations were noted. Additionally, changes in resuscitation status were noted. The predominant indication for PEG placement was dementia (52%). At PEG placement, 48% of patients had total functional impairment. Regardless of the severity of impairment, no patient's functional status improved after PEG. Nutritional status did not improve significantly. Mortality approached 50% and 60% at 12 and 18 months, respectively, and was significantly related to age, resuscitation status, and serum albumin concentration. All patients under 40 years of age at PEG survived, in contrast to 41.3% of patients over 40 years of age (P<0.001). Sixty-three percent of patients who were full code at PEG placement survived, in contrast to 10% of no code patients (P<0.001). Albumin 3.5 g/dl at PEG or thereafter was associated with improved survival (P<0.001) as compared to albumin <3.5 g/dl. PEG-related complications occurred in 34.7% of patients, and the first occurred four months after PEG. We conclude that realistic expectations of what PEG can accomplish be a factor in the decision to place a PEG tube in nursing home patients.     

Spinal anaesthesia but not general anaesthesia enhances neutrophil biocidal activity in hip arthroplasty patients

The purpose of this study was to compare neutrophil cidal activity during general or spinal anaesthesia. Assays were performed on neutrophils extracted from the blood of patients after surgery had been under way for one hour. First, the ability of the neutrophils to kill a standard laboratory strain of S. aureus was examined. Neutrophils extracted from the blood during surgery in the spinal anaesthetic group and incubated with the staphylococci for one hour killed twice as many bacteria than those from two groups of patients that received halothane or isoflurane general anaesthesia (P < 0.05). This effect persisted, to a lesser extent, in the spinal group neutrophils after two hours of incubation with the bacteria. Second, neutrophils from patients under the same conditions of surgery and anaesthesia were tested to examine the effect of the different anaesthetic techniques on neutrophil biocidal mechanisms. Neutrophils extracted during surgery in the spinal group released more superoxide in response to phorbol-12-myristate-13-acetate (PMA) than those from both groups of patients that received general anaesthesia (P < 0.05). It is concluded that there is an increased state of reactivity of the neutrophil cell membrane NADPH oxidase system in patients receiving spinal anaesthesia than in patients receiving general anaesthesia.     

Serotonin involvement in the antitumour and host effects of flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid

The relationship of serotonin (5-HT) receptors to the action of the experimental antitumour drugs flavone-8-acetic acid (FAA) and 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) was studied. Both FAA and 5,6-MeXAA are known to induce the synthesis of tumour necrosis factor- (TNF) and to stimulate nitric oxide synthesis in vivo, as measured by elevation of plasma nitrate. Serotonin potentiated the effect of a subtherapeutic dose of 5,6-MeXAA (20 mg/kg) as measured both by plasma nitrate increase and by growth delay of s.c. implanted colon 38 tumours. On the other hand, administration of the serotonin 5-hydroxytryptamine-2 (T-HT₂) antagonist cyproheptadine (20 mg/kg) inhibited both the plasma nitrate response and, to a lesser extent, the induction of tumour haemorrhagic necrosis by 5,6-MeXAA, FAA and TNF. Reduction of circulating plasma serotonin by pre-treatment withp-chlorophenylalanine and reserpine reduced the plasma nitrate response, but not the tumour necrosis response, to 5,6-MeXAA (30 mg/kg). It is suggested that serotonin is necessary for the induction of nitric oxide synthases and acts, either directly or indirectly, in concert with TNF. Serotonin agonists may have utility in increasing nitric oxide synthesis in response to TNF or to agents that induced TNF as part of their antitumour action.This research was supported by the Auckland Division of Cancer Society of New Zealand and the Health Research Council of New Zealand, by the Health Research Council of New Zealand and by the Ruth Spencer Medical Research Fellowship Trust.     

Current benzodiazepine issues

This article deals with some of the recent evidence bearing on the issues of the liability of benzodiazepines to lead to abuse, dependence, and adverse behavioral effects. Reviews of epidemiological, clinical and experimental literature indicated that the previous conclusion about abuse of these drugs still holds: the vast majority of the use of benzodiazepines is appropriate. Problems of nonmedical use arise nearly exclusively among people who abuse other drugs. Nevertheless, there are reasons for concern about patients who take benzodiazepines regularly for long periods of time. These drugs can produce physiological dependence when taken chronicaly, and although this does not appear to result in dose escalation or other evidence of psychological dependence, physiological dependence can result in patient discomfort if drug use is abruptly discontiniued. Also, physicians are currently prescribing shorter-acting benzodiazepines in preference to longer-acting benzodiazepines. The shorter-acting drugs can produce a more intense withdrawal syndrome following chronic administration. Furthermore, rates of use of benzodiazepines increase with age, and elderly patients are more likely than younger ones to take the drug chronically. The clearest adverse effect of benzodiazepines is impairment of memory. This, too, may be particular concern in older patients whose recall in the absence of drug is typically impaired relative to younger individuals, and who are more compromised following drug administration.This article was supported by USPHS Grant DA-00254 and by funding from Hoffmann-La Roche, Inc.     

Physician Response to Prenatal Substance Exposure

Objectives: To examine physician responses to suspected prenatal substance exposure and the reasons underlying these responses. Methods: National mail survey of practicing obstetricians and pediatricians who see neonates. Response rate: 63%. Results: More than 70% of physicians reported having ever suspected prenatal substance exposure. Response rates did not vary by specialty. Twenty-seven percent reported that they had never suspected prenatal substance exposure. The most common lifetime pattern (60%) was some response whenever prenatal substance exposure was suspected; next most common was no suspicion (27%). Just over 10% had a discretionary response: acting in some cases of suspected prenatal substance exposure but ignoring others. Two percent consistently ignored their suspicions. Getting help for the patient and protecting the fetus were the most common reasons to act. Among those who had ignored their suspicions, lack of sufficient evidence of substance use was the most often cited reason. There were some important specialty differences in reasons for response and non-response and in specific responses likely to be taken. Obstetricians are far more likely to provide the patient with information and get a substance use history; pediatricians are more inclined to involve outsiders. Conclusions: Obstetricians and pediatricians seem quite willing to act on their suspicions of prenatal substance exposure, and generally respond by taking positive actions. Specialty differences are few and reflect practice differences.     

Linking Clients from HIV Antibody Counseling and Testing to Prevention Services

The effectiveness of HIV antibody counseling and testing as a prevention intervention is limited: persons testing seronegative do not usually change their risk behaviors, some actually increase their risk behaviors, and decreases in risk behaviors are usually short-lived. Referrals to additional prevention and other needed services are therefore recommended, although the extent and determinants of referral provision for persons testing seronegative are unknown. We assessed the prevalence of referrals and the association between risk behaviors and prevention referrals among seronegatives. We reviewed HIV testing and referral data on all persons receiving confidential seronegative test results in San Francisco (SF) in the first 10 months of 1995 (n = 5,595), and gathered more detailed referral information at the municipal STD clinic from November 1995 through May 1996 (n = 747). The overall prevalence of referrals was low: a referral was given to 19.1% of the SF sample and 10.6% of the STD clinic sample; 15.4% of the SF sample and 5.9% of the STD clinic sample received a prevention referral. Injection drug users (IDUs) were the most likely to receive a prevention referral (48.5% of SF IDUs, 36.4% of STD clinic IDUs); men having sex with men and women with high-risk partners were also more likely to get a prevention referral than others. For SF IDUs, unsafe sex and needle sharing were not associated with an increased likelihood of receiving a prevention referral. Opportunities to link high-risk clients from counseling and testing to HIV prevention services are being missed. The referral component of HIV counseling and testing should be improved.     

Manic Psychosis and Catatonia Stemming from Systemic Lupus Erythematosus: Response to ECT

A 27-year-old woman with severe psychosis and mania associated with systemic lupus erythematosus was successfully treated with electroconvulsive therapy. Cyclophosphamide was given as an adjuvant. The use of electroconvulsive therapy in patients with lupus and psychiatric disorders is discussed.     

Assessment issues involving the families of trauma victims

This paper reviews the empirical literature on the clinically significant problems found within families containing a member with post-traumatic stress disorder. Recommendations are made regarding specific instruments that can be useful for evaluating marital and familial adjustment. Assessment issues concerning the need to weigh historical relationship factors vis-á-vis the influences of a traumatized family member are discussed. A multiple-gating model is presented for assessing different aspects of family dysfunction, and suggestions for future research and clinical directions are offered.