The 'Folic Acid Campaign': has the message got through? A questionnaire study.

There is now clear evidence that folic acid reduces the risk of neural tube defects. In February 1996 the Health Education Authority launched a publicity campaign to inform women of the benefits of periconceptual folic acid. We have surveyed 1000 women to assess the compliance of pregnant women with the Department of Health's recommendations about taking folic acid. Of the women, 761 (76%) said they knew about the benefits of folic acid but only 433 (43%) of them took it before pregnancy. Of the 567 women who did not take folic acid before conception, 227 had not planned their pregnancy and 239 did not know about the benefits. Of the 644 women who planned their pregnancy and knew about the benefits of folic acid before conception 211 still did not take folic acid pre-pregnancy. These findings have important implications for public policy and health professionals if the incidence of neural tube defect is to be reduced further.     

Antibiotic‐induced Cardiac Arrhythmias

This review aims to clarify the underlying risk of arrhythmia associated with the use of macrolides and fluoroquinolones antibiotics. Torsades de pointes (TdP) is a rare potential side effect of fluoroquinolones and macrolide antibiotics. However, the widespread use of these antibiotics compounds the problem. These antibiotics prolong the phase 3 of the action potential and cause early after depolarization and dispersion of repolarization that precipitate TdP. The potency of these drugs, as potassium channel blockers, is very low, and differences between them are minimal. Underlying impaired cardiac repolarization is a prerequisite for arrhythmia induction. Impaired cardiac repolarization can be congenital in the young or acquired in adults. The most important risk factors are a prolonged baseline QTc interval or a combination with class III antiarrhythmic drugs. Modifiable risk factors, including hypokalemia, hypomagnesemia, drug interactions, and bradycardia, should be corrected. In the absence of a major risk factor, the incidence of TdP is very low. The use of these drugs in the appropriate settings of infection should not be altered because of the rare risk of TdP, except among cases with high‐risk factors.     

DNA fusion vaccine designs to induce tumor‐lytic CD8+ T‐cell attack via the immunodominant cysteine‐containing epitope of NY‐ESO 1

The cancer/testis antigen NY‐ESO‐1 contains an immunodominant HLA‐A2‐binding peptide (SLLMWITQC), designated S9C, an attractive target for vaccination against several human cancers. As cysteine contains a reactive ? SH, the oxidation status of exogenous synthetic peptide is uncertain. We have designed tolerance‐breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to tumor‐derived peptide sequences (p.DOM‐peptide), placed at the C‐terminus for optimal immunogenicity. In a “humanized” HLA‐A2 preclinical model, p.DOM‐S9C primed S9C‐specific CD8+ T cells more effectively than adjuvanted synthetic peptide. A DNA vaccine encoding the full NY‐ESO‐1 sequence alone induced only weak S9C‐specific responses, amplified by addition of DOM sequence. The analog peptide (SLLMWITQL ) also primed peptide‐specific CD8+ T cells, again increased by DNA delivery. Importantly, T cells induced by S9C‐encoding DNA vaccines killed tumor cells expressing endogenous NY‐ESO‐1. Only a fraction of T cells induced by the S9L‐encoding DNA vaccines was able to recognize S9C and kill tumor cells. These data indicate that DNA vaccines mimic posttranslational modifications of ? SH‐containing peptides expressed by tumor cells. Instability of synthetic peptides and the potential dangers of analog peptides contrast with the ability of DNA vaccines to induce high levels of tumor‐lytic peptide‐specific CD8+ T cells. These findings encourage clinical exploration of this vaccine strategy to target NY‐ESO‐1.     

Analysis of Treatment Results for Floor‐of‐Mouth Cancer

Objective This study reports the results of treating floor‐of‐mouth cancer with five different treatment modalities with long‐term follow‐up. Study Design Retrospective study of 280 patients with floor‐of‐mouth cancer treated in the Department of Otolaryngology—Head and Neck Surgery at Washington University Medical School (St. Louis, MO) from 1960 to 1994. Methods Patients with biopsy‐proven squamous cell carcinoma of the floor of mouth who were previously untreated were treated with curative intent by one of five modalities and were all eligible for 5‐year follow‐up. The treatment modalities included local resection alone, composite resection alone (with neck dissection), radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow‐up parameters were studied using standard statistical analysis to determine statistical significance. Results The overall 5‐year disease‐specific survival (DSS) was 56% with death due to tumor in 44% of patients. The 5‐year cumulative disease‐specific survival (CDSS) was 0.61 (Kaplan‐Meier probability) with a mean of 8.3 years and a median of 9.7 years. The DSS by treatment modality included local resection (76%), composite resection (63%), radiation therapy (43%), local resection with radiation therapy (61%), and composite resection with radiation therapy (55%). Overall, there was no significant difference in DSS by treatment modality. Recurrence at the primary site (41%) was the most common site of treatment failure. Nineteen percent of patients had recurrence in the neck. Eighty‐eight percent of initial recurrences occurred within 60 months after the onset of treatment. Metastasis to a distant site occurred in 30% of patients. Twenty percent of these patients had second primary cancers, and 53% of these patients died of their second primary cancers. Conclusions Significantly improved 5‐year DSS was seen in the patients with clear margins, early clinical tumor stage, and negative nodes. Significantly decreased 5‐year survival was seen in the patients with involved margins, advanced clinical tumor stage, positive nodes, and tumor recurrence. Patients with no clinically positive nodes (cN0) can be observed safely for regional nodal disease and subsequent positive nodes can be treated as they occur with no adverse affect on survival. Because of high recurrence rates at the primary site and neck, and an increased rate of both distant metastasis and the development of second primary cancers, patients should be monitored closely for a minimum of at least 5 years.     

Release of endogenous and radioactive purines from the rabbit retina

The adenine nucleotide pool of rabbit retina was labeled by an intravitreal injection in vivo of [3H]adenosine. Practically all the radioactivity was retained in the form of adenine nucleotides. The relative proportion of [3H]adenine nucleotides was the same as that of endogenous nucleotides. Potassium depolarization (43.6 mM) in vitro caused a rapid increase in the rate of release of radioactive purines. The radioactive material was composed of hypoxanthine, xanthine, inosine and trace amounts of adenine, adenosine and adenine nucleotides. The release of radioactive purines was delayed and reduced by the addition of the nucleoside inhibitor dipyridamole suggesting that the purines may be released in the form of nucleosides. Similarly, the addition of the ecto 5'-nucleotidase inhibitor alpha, beta-methylene ADP (AOPCP) did not alter the release of radioactivity or the composition of the released purines. Endogenous hypoxanthine, xanthine and inosine could be detected in the effluents, but there was only a very modest increase following potassium depolarization. There was a slight, but significant, decrease in the release of endogenous adenosine and increase in AMP after AOPCP. It is concluded that there is an intensive uptake and phosphorylation of adenosine in the rabbit retina. Depolarization induces release of radioactive purine nucleosides and bases. Most of these compounds appear to be released as such, but in addition there may be a small (maximally a few per cent of the total) fraction of the purines that are released as nucleotides.     

Cocaine dependence and d2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior.

Striatal dopamine D2 receptors have been implicated in the neurobiology of cocaine addiction. Previous imaging studies showed reduced striatal D2 receptor availability in chronic cocaine abusers, and animal studies suggested that low D2 receptor availability promotes cocaine self-administration. Here, D2 receptor availability was assessed with positron emission tomography (PET) and [11C]raclopride in the limbic, associative, and sensori-motor subdivisions of the striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and 17 matched healthy control (HC) subjects. In addition, the relationship between regional D2 receptor availability and behavioral measures obtained in cocaine self-administration sessions was investigated in CCD subjects. [11C]Raclopride binding potential was significantly reduced by 15.2% in the limbic striatum, 15.0% in the associative striatum, and 17.1% in the sensori-motor striatum in CCD subjects compared to HC subjects. In CCD subjects, no relationship was detected between D2 availability in striatal regions and either the positive effects of smoked cocaine or the choice of cocaine over an alternative reinforcer (money) following a priming dose of cocaine (a laboratory model of relapse). Thus, this study confirms previous reports of a modest decrease in D2 receptor availability in CCD subjects, and establishes that this decrease is generalized throughout the striatum. However, this study failed to demonstrate a relationship between D2 receptor availability and cocaine-induced cocaine-taking behavior. Additional research is warranted to unravel potential neurobiological traits that might confer vulnerability to relapse in detoxified CCD subjects.     

Cell kill kinetics with hydroxyurea.

The effects of various concentrations of hydroxyurea (HU) on a human lymphoid cell line in exponential growth phase have been studied using a combination of methods, including determination of the total and viable cell counts; the cells relative DNA content, measured in a flow microfluorimeter after staining with a fluorescent Feulgen technique; the mitotic index; and the percentage of cells incorporating thymidine-3H (TdR-3H) during brief and continuous exposure to the isotope both in the presence and absence of colcemid. A significant redistribution of the cells in the various phases of the cell cycle occurred during the first 24 hr of continuous treatment with 10(-3) M and 10(-2) M HU as follows: (1) division of cells in G2; (2) depletion of mid and late S phase cells due to early cell death; (3) movement of most G1 cells at a normal rate into early S phase where they accumulate; and (4) arrest of the remaining cells in G1, which represented the surviving population after treatment for 96 hr or longer. After removal of the drug, the cell fraction blocked in early S phase progressed semisynchronously through S, but many of the cells were unable to complete division. Their capacity to recover depended on the drug concentration and duration of exposure, but in general the cellular injury caused by HU was more reversible than that caused by "equivalent" concentrations of arabinosylcytosine.     

Acid-base disturbances in liver disease

There are several important associations between the liver and acid-base balance. First, primarily because of its metabolism of certain cationic amino acids and organic acid anions, particularly lactate, the liver has a surprisingly important influence on normal acid-base homeostasis. Second, in the presence of the necessary pathogenic milieu, the liver may produce a life-threatening number of hydrogen ions. Examples include accelerated ketogenesis during insulinopenic states, or lactate production during severe hepatic parenchymal hypoxia. Third, patients with various types of liver disease, both acute and chronic, often develop complicating acid-base disturbances. In addition, liver disease may predispose the patient to a particular acid-base disorder such as phenformin-induced lactic acidosis. Finally, the acid-base disturbance may be a complication of therapy, as when diuretic therapy directed at ascites results in metabolic alkalosis.     

Prospective study of the incidence and outcome of intra-abdominal hypertension and the abdominal compartment syndrome

BACKGROUND: Intra-abdominal hypertension has been recognized as a source of morbidity and mortality in the traumatized patient following laparotomy. Multiple organ dysfunction attributable to intra-abdominal hypertension has been called the abdominal compartment syndrome. The epidemiology and characteristics of these processes remain poorly defined. METHODS: Intra-abdominal pressure was measured prospectively in all patients admitted to a trauma intensive care unit over 9 months. Data were gathered on all patients with intra-abdominal hypertension. RESULTS: Some 706 patients were evaluated. Fifteen (2 per cent) of 706 patients had intra-abdominal hypertension. Six of the 15 patients with intra-abdominal hypertension had abdominal compartment syndrome. Half of the patients with abdominal compartment syndrome died, as did two of the remaining nine patients with intra-abdominal hypertension. Patients with abdominal compartment syndrome had a mean intra-abdominal pressure of 42 mmHg compared with 26 mmHg in patients with intra-abdominal hypertension only (P < 0.05). CONCLUSION: The incidence of intra-abdominal hypertension and abdominal compartment syndrome was 2 and 1 per cent respectively. Intra-abdominal hypertension did not necessarily lead to abdominal compartment syndrome, and often resolved without clinical sequelae. Abdominal compartment syndrome did not occur in the absence of earlier laparotomy. Abdominal compartment syndrome was associated with a marked increase in intra-abdominal pressure (above 40 mmHg).