Should embryos with autosomal monosomy by preimplantation genetic testing for aneuploidy be transferred?: Implications for embryo selection from a systematic literature review of autosomal monosomy survivors.

OBJECTIVE: To review the literature for survival and phenotypes of liveborns with autosomal monosomy to inform decisions regarding transfer of in vitro fertilization-derived embryos reported as monosomic on preimplantation genetic testing for aneuploidy (PGT-A). METHOD: Ovid-Medline and EMBASE were systematically searched to identify published case reports of liveborn individuals with autosomal monosomy, full or mosaic, for a whole chromosome. RESULTS: Fifty-three reports describing 56 individuals with autosomal monosomy met the selection criteria: 1 case each of monosomy 14 and 16, 3 each for monosomy 15 and 18, 1 for group "E", 5 for monosomy 20, 24 for monosomy 21, 7 for monosomy 22, and eleven for a "G" group chromosome. There were no reports with monosomy for the larger chromosomes 1 through 13, nor for chromosomes 17 or 19, autosomes with highest gene density. Most reported individuals had severe handicaps and died in infancy with some surviving longer. CONCLUSION: Given potential for survival of handicapped individuals with autosomal monosomy for chromosomes 14, 15, 16, 18, 20, 21, and 22, low priority should be given to transfer of embryos apparently monosomic for these chromosomes. Couples electing transfer of monosomic embryos should consider amniocentesis for ongoing pregnancies but should be informed of its limitations.

Non-radiation risk factors for leukemia: A case-control study among chornobyl cleanup workers in Ukraine.

BACKGROUND: Occupational and environmental exposure to chemicals such as benzene has been linked to increased risk of leukemia. Cigarette smoking and alcohol consumption have also been found to affect leukemia risk. Previous analyses in a large cohort of Chornobyl clean-up workers in Ukraine found significant radiation-related increased risk for all leukemia types. We investigated the potential for additional effects of occupational and lifestyle factors on leukemia risk in this radiation-exposed cohort. METHODS: In a case-control study of chronic lymphocytic and other leukemias among Chornobyl cleanup workers, we collected data on a range of non-radiation exposures. We evaluated these and other potential risk factors in analyses adjusting for estimated bone marrow radiation dose. We calculated Odds Ratios and 95% Confidence Intervals in relation to lifestyle factors and occupational hazards. RESULTS: After adjusting for radiation, we found no clear association of leukemia risk with smoking or alcohol but identified a two-fold elevated risk for non-CLL leukemia with occupational exposure to petroleum (OR=2.28; 95% Confidence Interval 1.13, 6.79). Risks were particularly high for myeloid leukemias. No associations with risk factors other than radiation were found for chronic lymphocytic leukemia. CONCLUSIONS: These data - the first from a working population in Ukraine - add to evidence from several previous reports of excess leukemia morbidity in groups exposed environmentally or occupationally to petroleum or its products.

Isoniazid urine spectrophotometry for prediction of serum pharmacokinetics in adults with TB.

BACKGROUND: Isoniazid (INH) is an important drug in many TB regimens, and unfavorable treatment outcomes can be caused by suboptimal pharmacokinetics. Dose adjustment can be personalized by measuring peak serum concentrations; however, the process involves cold-chain preservation and laboratory techniques such as liquid chromatography (LC)/mass spectrometry (MS), which are unavailable in many high-burden settings. Urine spectrophotometry could provide a low-cost alternative with simple sampling and quantification methods. METHODS: We enrolled 56 adult patients on treatment for active TB. Serum was collected at 0, 1, 2, 4, 6, and 8 h for measurement of INH concentrations using validated LC-MS/MS methods. Urine was collected at 0-4, 4-8, and 8-24 h intervals, with INH concentrations measured using colorimetric methods. RESULTS: The median peak serum concentration and total serum exposure over 24 h were 4.8 mg/L and 16.4 mg*hour/L, respectively. Area under the receiver operator characteristic curves for urine values predicting a subtherapeutic serum concentration (peak <3.0 mg/L) were as follows: 0-4 h interval (AUC 0.85, 95% CI 0.7-0.96), 0-8 h interval (AUC 0.85, 95% CI 0.71-0.96), and 0-24 h urine collection interval (AUC 0.84, 95% CI 0.68-0.96). CONCLUSION: Urine spectrophotometry may improve feasibility of personalized dosing in high TB burden regions but requires further study of target attainment following dose adjustment based on a urine threshold.

CONTEXTE: L'isoniazide (INH) est un médicament important dans de nombreux schémas thérapeutiques contre la TB, et des résultats thérapeutiques défavorables peuvent être dus à une pharmacocinétique sous-optimale. L'ajustement de la dose peut être personnalisé en mesurant les concentrations sériques maximales ; cependant, le processus implique la conservation de la chaîne du froid et des techniques de laboratoire telles que la chromatographie liquide (LC)/spectrométrie de masse (MS), qui ne sont pas disponibles dans de nombreuses régions à forte charge de morbidité. La spec-trophotométrie urinaire pourrait constituer une alternative peu coûteuse avec des méthodes d'échantillonnage et de quantification simples. MÉTHODES: Nous avons recruté 56 patients adultes sous traitement pour une TB active. Le sérum a été prélevé à 0, 1, 2, 4, 6 et 8 h pour mesurer les concentrations d'INH à l'aide de méthodes LC-MS/MS validées. L'urine a été prélevée à des intervalles de 0­4, 4­8 et 8­24 h, et les concentrations d'INH ont été mesurées à l'aide de méthodes colorimétriques. RÉSULTATS: La concentration sérique maximale médiane et l'exposition sérique totale sur 24 h étaient respectivement de 4,8 mg/L et de 16,4 mg*heure/L. L'aire sous les courbes caractéristiques de l'opérateur récepteur a été mesurée à l'aide de méthodes color-imétriques. Les aires sous les courbes caractéristiques des récepteurs pour les valeurs urinaires prédisant une concentration sérique sous-thérapeutique (pic <3,0 mg/L) étaient les suivantes : intervalle 0­4 h (AUC 0,85 ; IC 95% 0,7­0,96), intervalle 0­8 h (AUC 0,85 ; IC 95% 0,71­0,96), et intervalle de collecte d'urine 0­24 h (AUC 0,84 ; IC 95% 0,68­0,96). CONCLUSION: La spectrophotométrie urinaire peut améliorer la faisabilité d'un dosage personnalisé dans les régions à forte charge de TB, mais nécessite une étude plus approfondie de l'atteinte de la cible après l'ajustement de la dose sur la base d'un seuil urinaire.

The Ukrainian-American study of leukemia and related disorders among Chornobyl cleanup workers from Ukraine: I. Study methods.

There are relatively few data on the risk of leukemia among those exposed to external radiation during cleanup operations after the Chornobyl nuclear accident, and results have not been consistent. To investigate this further, we assembled a cohort of 110,645 male cleanup workers from Ukraine and identified cases of leukemia occurring during the period 1986 to 2000. Detailed interviews were conducted and individual bone marrow doses estimated using a new time-and-motion method known as RADRUE described in companion paper II. For the initial analyses we used a nested case-control approach with a minimum of five controls per case, matched for year of birth, oblast (region) of registration, and residence. All identified cases were reviewed by an international panel of experts; 87 of 111 were confirmed. The dose-response analysis and results are given in companion paper III. As background, we describe herein the design, procedures, outcome of case finding and confirmation, control selection, dose estimation and interviewing of subjects.

Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemoprotection in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation.

PURPOSE: Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product and, therefore, are particularly susceptible to killing by MDR-sensitive drugs, such as vinca alkaloids, anthracyclines, podophyllins, and paclitaxel and its congeners. Here we report the results of a phase I clinical trial that tested the safety and efficacy of transfer of the human multiple drug resistance (MDR1, MDR) gene into hematopoietic stem cells and progenitors in bone marrow as a means of providing resistance of these cells to the toxic effects of cancer chemotherapy. PATIENTS AND METHODS: Up to one third of the harvested cells of patients who were undergoing autologous bone marrow transplantation as part of a high-dose chemotherapy treatment for advanced cancer were transduced with an MDR cDNA-containing retrovirus; these transduced cells were reinfused together with unmanipulated cells after chemotherapy. RESULTS: High-level MDR transduction of erythroid burst-forming unit (BFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) derived from transduced CD34+ cells was shown posttransduction and prereinfusion. However, only two of the five patients showed evidence of MDR transduction of their marrow at a low level at 10 weeks and 3 weeks, respectively, posttransplantation. The cytokine-stimulated transduced cells may be out-competed in repopulation by unmanipulated normal cells that are reinfused concomitantly. The MDR retroviral supernatant that was used was shown to be free of replication-competent retrovirus (RCR) before use, and all tests of patients' samples posttransplantation were negative for RCR. In addition, no adverse events with respect to marrow engraftment or other problems related to marrow transplantation were encountered. CONCLUSION: These results indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene.

Retroviral transfer and expression of the human multiple drug resistance (MDR) gene in peripheral blood progenitor cells.

The multiple drug resistance (MDR) gene P-glycoprotein product is a transmembrane efflux pump that prevents toxicity of a variety of chemotherapeutic agents, including the anthracyclines, Vinca alkaloids, podophyllins, and taxol. The bone marrow toxicity of these drugs is due to the low or absent expression of MDR in marrow cells. Transfer and expression of the human MDR gene into bone marrow progenitors should prevent this toxicity. We report here the efficient transfer and expression of the MDR gene by retroviral-mediated gene transfer into CD34(+) cells isolated from peripheral blood progenitor cells (PBPCs), comparable to that obtained using bone marrow-derived progenitors. Optimal MDR transduction of these PBPC-derived cells requires exposure to growth factors and a period of preincubation. In addition, we demonstrate that we can transduce up to 100% of progenitor cells derived from PBPCs and can protect up to 25% of these progenitors from a dose of taxol toxic to untransduced controls.

How do nurses experience working with adolescents with a diagnosis of 'personality disorder' or 'emerging personality disorder'?

Nurses experience adults with a diagnosis of 'personality disorder' ('PD') as challenging, but nothing is known of their experiences working with young people with a diagnosis of 'PD' or 'emerging PD'. This study aimed to explore the experiences of nurses with this group. Six nurses were interviewed individually and the transcripts analysed employing interpretative phenomenological analysis. Two themes were identified: emotional impact, and conflict and need for support. Participants described powerful emotional responses and heavy time demands as particular challenges. They also reflected on tensions that arose in the wider team and service context. The importance of reflective space, training and the need for specialist approaches, such as therapeutic input, was emphasized by all participants. The study's findings suggest that while there are some similarities to adult services, there are also issues specific to nursing adolescents with 'PD', which merit further attention, including the implications of the lack of diagnostic clarity for treatment approaches and the difficult interpersonal dynamics of the condition. Recommendations for practice include additional training in relation to the theoretical understanding of diagnosis itself and in working therapeutically with young people with the diagnosis, employing approaches that have been found to be useful in adult services.

Lithium pharmacokinetics in the obese.

INTRODUCTION: The purpose of this study was to investigate the disposition of lithium in obese subjects compared with the disposition in normal weight volunteers. METHODS: Ten obese volunteers (weight, 110.2 +/- 28.6 kg) were compared with eight evaluable normal weight volunteers (weight, 63.1 +/- 6.6 kg). Oral lithium citrate (31.4 mEq) was administered and blood samples were obtained over a 48-hour period. Creatinine clearance (CLCR) was determined from a 12-hour urine collection. Total body water was determined by the deuterium oxide dilution method. RESULTS: The clearance of lithium (CLLi) for the obese group was significantly greater than that for the control group (33.9 +/- 7.0 ml/min versus 23.0 +/- 6.2 ml/min; p = 0.005). The steady-state volume of distribution (VSS) for the obese group was significantly less than that for the control group (0.42 +/- 0.09 L/kg versus 0.66 +/- 0.16 L/kg; p = 0.001). For the combined group, VSS was significantly correlated with ideal body weight and fat free mass but not with total body weight. The CLLi was significantly correlated with total body weight, but not with CLCR. CONCLUSIONS: The pharmacokinetic properties of lithium were significantly different for the obese subjects compared with those the normal weight control subjects. At steady state there is a direct proportionality between CLLi and the dose required to achieve a given serum lithium concentration, therefore the results of this study suggest that obese patients may require larger lithium maintenance doses than nonobese patients.

Amino acid alcohols: growth inhibition and induction of differentiated features in melanoma cells.

The effects of a series of D- and L-amino acid alcohols on the proliferation and phenotypic expression of B16 mouse melanoma cells were evaluated. B16 melanoma cells were incubated for different time intervals in the presence of D- or L-phenylalaninol (PHE), D- or L-alaninol (AL), D- or L-leucinol (LE), L-histidinol (HIS), L-tyrosinol (TYR) and L-methioninol (MET). All agents, including the D or L configuration, induced an anti-proliferative effect, although of considerably different magnitude. D-PHE was the most active growth inhibitor. The growth inhibitory effects were accompanied by phenotypic alterations, which included morphological changes and enhancement in the activities of NADPH cytochrome c reductase and tau-glutamyl transpeptidase. These phenotypic alterations correlated with the growth inhibitory effects of the different agents and seem to reflect a higher differentiated state.

Trisomy 2p syndrome: a fetus with anencephaly and postaxial polydactyly.

We report on a male fetus with partial trisomy 2p21-2pter and monosomy 15q26-15qter due to t(2,15)(p21;q26). This fetus had a typical trisomy 2p phenotype including minor facial anomalies, musculoskeletal defects and two unusual findings: polydactyly and anencephaly. The observation of anencephaly adds support to the theory that genetic material mapping to chromosome band 2p24 is involved in neural tube development. In addition, we propose that a gene on 2p23 may play a role in the morphogenetic patterning of hands and feet.

Cohort comparison study of children whose mothers have acquired immunodeficiency syndrome and children of well inner city mothers.

The virus or viruses (human immunodeficiency virus) associated with the acquired immunodeficiency syndrome may be transmitted in utero or perinatally from an infected mother to her baby. Infected adults may remain asymptomatic for months to years, during which time a mother could transmit the virus. It is not known to what degree a mother may transmit the virus perinatally or whether postnatal transmission is possible. We studied a cohort of children whose mothers had been reported to have acquired immunodeficiency syndrome, comparing human immunodeficiency virus-seropositive with seronegative children as well as a cohort of inner city children with similar socioeconomic characteristics whose mothers are well. Three (12%) of 25 children whose mothers have acquired immunodeficiency syndrome were seropositive compared with none of 44 children whose mothers were well. The seropositive children had lower T4A:T8 lymphocyte ratios than children in the other groups. Nine children of affected mothers were young enough to have been born within their mother's incubation period and were seronegative and well. When compared with seronegative children the seropositive children did not have greater contact with their ill mothers, either in types of physical interaction or in length of time lived together. Although this study cannot preclude the possibility of postnatal nonsexual transmission, it does present evidence against it.

An improved method for the quantitation of A2 hemoglobin utilizing cellulose acetate electrophoresis and densitometry.

An improved method of A2 quantitation by cellulose acetate electrophoresis is describes. Densitometry is performed on uncleared membranes. The height of the peak obtained for the A2 band is compared with a standard curve derived from peaks obtained by serial dilutions of hemoglobin. Noral A2 hemoglobin as measured by this method is 2.55 percent plus or minus 0.60 (2 S.D.). Twenty patients samples were run in parallel with a column chromatographic method. Eight samples were found to contain elevated A2 levels by the column method. The same eight samples were correctly identified by the electrophoretic technic.

The eighth-month fetus: classical sources for a modern superstition.

Among obstetric patients from diverse backgrounds, we found a superstition that the prognosis for preterm infants born at eight months' gestation is poorer than for those born at seven months. After several women on a high-risk inpatient unit spontaneously expressed fears caused by this belief, we investigated its origin. A treatise attributed to Hippocrates is devoted to the idea, which appears to have been current in the Greek world by the fifth century BC. The doctrine was elaborately developed by subsequent Greek physicians and philosophers. It appears in the Talmud and in medieval texts, as well as in early modern medical writings. The unquestioning citation of a dogma of the Ancients until modern times is a common phenomenon in medical history. The persistence of this ancient scientific doctrine as an "old wives' tale" causing inappropriate patient anxiety makes it interesting to the modern obstetrician.

Systemic prophylactic antibiotics in elective biliary surgery.

We tested the effectiveness of prophylactic antibiotics in elective cholecystectomy in 105 patients in a single-blind, controlled randomized trial. Fifty-six patients received prophylactic antibiotics and 49 patients entered the control group. Of the patients who received prophylactic antibiotics, 3.6% had wound infections, v24.5% in the control group. The rate of wound infection in patients with positive bile cultures, diabetes, appendectomies, and choledochotomies was 24.4%, v 3.4% in the group who had cholecystectomies only, with negative bile cultures and no diabetes. We concluded that prophylactic antibiotics are effective in patients with high-risk factors such as diabetes mellitus, exploration of the choledochus, and appendectomy, and in patients with positive bile cultures.

Achievements of physical therapy in patients after modified radical mastectomy compared with quadrantectomy, axillary dissection, and radiation for carcinoma of the breast.

Flexion of the shoulder, abduction, and external rotation in 90 degrees abduction are impaired after operations for breast cancer. We compared postoperative range of motion in 27 patients who underwent modified radical mastectomy and 21 patients who underwent quadrantectomy with axillary dissection and radiation therapy. The patients in the quadrantectomy group demonstrated a significantly higher range of flexion on postoperative day 1 and the day of suture removal. After 3 months, all patients had regained their preoperative range of flexion, with no difference between the groups. The better compliance of the quadrantectomy group to physical therapy may indicate that they suffer less pain and require a briefer or less intensive course of physical therapy.

Autologous fibrin glue from intraoperatively collected platelet-rich plasma.

A simple and inexpensive means of creating autologous fibrin glue is described that avoids the potential disadvantages of conventionally obtained material. This improvement may allow more widespread use of fibrin glue for operative bleeding.

Inversion (16)(p13q22) in tumor cells of sigmoid colon.

We report on the cytogenetic findings in direct preparations of two tumors of the sigmoid colon. Respectively, they had a near-triploid and a near-tetraploid constitution and relative numerical and other inconstant chromosomal imbalances. The only constant chromosomal structural anomaly apparently was inversion of chromosome #16, inv(16)(p13q22), which was found in all the cells examined. This rearrangement has been found to be associated with a type of acute myelomonocytic leukemia type M4. We suggest that an etiologic clastogenic (and oncogenic) agent responsible for this rearrangement may eventually be the cause of various kinds of malignancy.

Familial fragile 8q22 involved as a cancer breakpoint in cells of a large bowel tumor.

A familial fragile 8q22 and an interferon-induced fragile 16q22 were found in two sisters. Eight years previously, both sisters developed an endometrial adenocarcinoma and now one of them presented with an adenocarcinoma of the colon. An 8q22 deletion was found in all the cells of the colonic tumor and seemed to be the primary initiating change. Other nonrandom and possibly promoting aberrations were also present, among others, a 16q22 deletion. The possibility exists that a familial fragile 8q22 may predispose to cancer and a fragile 16q22 may have promoting capacities.

Involvement of chromosome 22 in a Merkel cell carcinoma in a patient with a previous meningioma.

The relatively simple cytogenetic findings in an aggressive metastatic Merkel cell carcinoma are reported. Deletion 2p was found in 100% of the cells. Nevertheless, this was considered a secondary (metastatic?) change because the same aberration has been found in several other kinds of malignancy. The involvement of chromosome 22 [del(22q) and -22] in 85% of the cells seemed more intriguing, considering the fact that the Merkel cell carcinoma followed a previous meningioma.

Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings.

STUDY OBJECTIVE: To compare the absolute bioavailability of phenytoin (PHT) sodium solution and PHT acid suspension in healthy volunteers receiving continuously infused enteral feedings. DESIGN: Randomized, open-label, single-dose, three-period crossover study. SETTING: University clinical research center. SUBJECTS: Ten healthy volunteers age 23-43 years. INTERVENTIONS: The three phases of the study were separated by at least 7 days. During phase A, subjects received PHT sodium 435 mg intravenously over 30 minutes. During phases B and C, subjects had a nasogastric feeding tube placed through which PHT acid suspension 400 mg and PHT sodium solution 435 mg were administered, respectively. For phases B and C, continuous enteral feedings were given by feeding tube for 14 hours before and after the PHT dose. Blood samples were collected over 72 hours after each PHT dose, and the serum was analyzed for PHT. MEASUREMENTS AND MAIN RESULTS: The rate and extent of PHT absorption and PHT pharmacokinetics were determined using an empirical quadratic function of time method. Bioavailability, rate of absorption, maximum concentration (Cmax), and time to maximum concentration (Tmax) were compared for the two enteral doses by paired Student's t test. There were no significant differences in bioavailability for PHT acid suspension and PHT sodium solution (0.88 +/- 0.15 vs 0.91 +/- 0.7, p=0.57, 90% CI -0.14-0.071). The Cmax was greater (7.4 +/- 0.9 mg/L vs 5.5 +/- 1.7 mg/L, p=0.019) and Tmax was less (2.5 +/- 3.8 vs.14.8 +/- 11.2 hrs, p=0.004) for the sodium solution. The time to 50% fractional absorption (0.33 +/- 0.08 vs 3.2 +/- 2.4 hrs, p=0.004) and 90% fractional absorption (7.9 +/- 6.2 vs 22.3 +/- 17.2 hrs, p=0.021) was also significantly shorter for the sodium solution. CONCLUSION: The absolute bioavailability of the two dosage forms of PHT administered with concomitant enteral feedings were not significantly different, however, the absorption patterns were significantly different, with the sodium solution being more rapidly absorbed.