Sex differences in acute health service contact after release from prison in Australia: a data linkage study.

OBJECTIVES: Women released from prison typically experience worse health outcomes than their male counterparts. We examined sex differences in the patterns, characteristics, and predictors of acute health service contact (AHSC) (i.e. ambulance and/or emergency department use) after release from prison. STUDY DESIGN: Data linkage study. METHODS: Baseline survey data from 1307 adults (21% women) within six weeks of expected release from prisons in Queensland, Australia (2008-2010) were linked prospectively with state-wide ambulance and emergency department, correctional, mental health, and death records. Crude and adjusted incidence rates and incidence rate ratios of AHSC were calculated overall and by sex. An Andersen-Gill model was fit to examine whether sex predicted AHSC. The interaction effect between sex and each model covariate was tested. RESULTS: The crude incidence rates of AHSC after release from prison were 1.4 (95% confidence interval [CI]: 1.3-1.5) and 1·1 (95%CI: 1.1-1.2) per person-year for women and men, respectively. The relationship between perceived physical health-related functioning at the baseline and AHSC was modified by sex (P = 0·039). The relationship between perceived health-related functioning and AHSC also differed among women. Compared to women who perceived their physical health as fair or good at the baseline, women who perceived their physical health as poor were at greater risk of AHSC (hazard ratio = 2.4, 95%CI: 1.4-3·9, P = 0.001) after release from prison. CONCLUSIONS: Among people released from prison, women's and men's AHSC differs depending on how they perceive their own physical health. The specific needs of women and men must be considered in transitional support policy and planning to improve their health outcomes.

Pharmacological treatment initiation for type 2 diabetes in Australia: are the guidelines being followed?

AIM: To determine the patterns and predictors of pharmacological treatment initiation for type 2 diabetes and whether treatment initiation is consistent with Australian clinical practice guidelines that recommend metformin monotherapy. METHODS: Individuals aged 40-99 years initiating a non-insulin type 2 diabetes medication between July 2013 and February 2018 were identified from a 10% random national sample of pharmacy dispensing data. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the predictors of initiating sulfonylurea monotherapy, non-guideline monotherapy and combination therapy compared with metformin monotherapy. Predictors included age, sex, initiation year and comorbidities determined using the Rx-Risk comorbidity index. RESULTS: Of the 47 860 initiators, [47% women, mean age 60.7 (sd 12.1) years], 85.8%, 4.6%, 1.9% and 7.7% received metformin monotherapy, sulfonylurea monotherapy, non-guideline monotherapy and combination therapy, respectively. Increasing age was associated with increasing odds of initiating sulfonylurea monotherapy and non-guideline monotherapy. Combination therapy initiation was less likely in women (OR 0.74, 95% CI 0.69-0.79) and people with more comorbidities (e.g. OR 0.36, 95% CI 0.29-0.44 for seven or more comorbidities vs. no comorbidities) but more likely in congestive heart failure (OR 1.42, 95% CI 1.22-1.65), cerebrovascular disease (OR 1.50, 95% CI 1.32-1.69) and dyslipidaemia (OR 1.29, 95% CI 1.19-1.40). CONCLUSION: Treatment initiation in Australia is largely consistent with clinical practice guidelines, with 86% of individuals initiating metformin monotherapy. Initiation on combination therapy was more common in men and in those with fewer comorbidities.

Using artificial intelligence algorithms to identify existing knowledge within the back pain literature.

PURPOSE: Artificial intelligence algorithms can now identify hidden data patterns within the scientific literature. In 2019, these algorithms identified a thermoelectric material within the pre-2009 chemistry literature; years before its discovery in 2012. This approach inspired us to apply this algorithm to the back pain literature as the cause of back pain remains unknown in 90% of cases. METHODS: We created a subset of all PubMed abstracts containing "back" and "pain" and then trained the Word2vec algorithm to predict word proximity. We then identified word pairings having high vector proximities between three spinal domains: anatomy, pathology and treatment. We plotted both between-domain and within-domain proximities then used the highest proximity pairs as ground truths in analogy testing to identify known associations (e.g., Canal is to Stenosis as Multifidus is to ?) RESULTS: We found  50,038 abstracts resulting in 27,984 unique words and 108,252 instances of "back pain". Ground truth pairings ranged in proximity from 0.86 to 0.70. Plotting revealed unique proximity representations between the three spine domains. From analogy testing, we identified 13 known word associations (pars_interarticularis is to stress_reaction as nerve_root is to compression). CONCLUSIONS: Artificial intelligence algorithms can successfully extract complex concepts from back pain literature. While use of AI algorithms to discover potentially unknown word associations requires future validation, our results provide investigators with a novel tool to generate new hypotheses regarding the origins of LBP and other spine related topics. To encourage use of these tools, we have created a free web-based app for investigator-driven queries.

Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer.

BACKGROUND: KRAS mutations in NSCLC are associated with a lack of response to epidermal growth factor receptor inhibitors. Selumetinib (AZD6244; ARRY-142886) is an oral selective MEK kinase inhibitor of the Ras/Raf/MEK/ERK pathway. PATIENTS AND METHODS: Advanced nonsmall-cell lung cancer (NSCLC) patients failing one to two prior regimens underwent KRAS profiling. KRAS wild-type patients were randomized to erlotinib (150 mg daily) or a combination of selumetinib (150 mg daily) with erlotinib (100 mg daily). KRAS mutant patients were randomized to selumetinib (75 mg b.i.d.) or the combination. The primary end points were progression-free survival (PFS) for the KRAS wild-type cohort and objective response rate (ORR) for the KRAS mutant cohort. Biomarker studies of ERK phosphorylation and immune subsets were carried out. RESULTS: From March 2010 to May 2013, 89 patients were screened; 41 KRAS mutant and 38 KRAS wild-type patients were enrolled. Median PFS in the KRAS wild-type arm was 2.4 months [95% confidence interval (CI) 1.3-3.7] for erlotinib alone and 2.1 months (95% CI 1.8-5.1) for the combination. The ORR in the KRAS mutant group was 0% (95% CI 0.0% to 33.6%) for selumetinib alone and 10% (95% CI 2.1% to 26.3%) for the combination. Combination therapy resulted in increased toxicities, requiring dose reductions (56%) and discontinuation (8%). Programmed cell death-1 expression on regulatory T cells (Tregs), Tim-3 on CD8+ T cells and Th17 levels were associated with PFS and overall survival in patients receiving selumetinib. CONCLUSIONS: This study failed to show improvement in ORR or PFS with combination therapy of selumetinib and erlotinib over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. The association of immune subsets and immune checkpoint receptor expression with selumetinib may warrant further studies.

The use of human patient simulators to enhance clinical decision-making of nursing students.

INTRODUCTION: One of the newest teaching modalities in health education is the use of human patient simulators (HPS). A simulation scenario creates a software program vignette in which nursing, medical, and other students interact with a manikin to practice caring for patients in a risk-free environment. Although used extensively in schools of nursing, there is little research that examines if these expensive simulators improve the clinical decision-making ability of nursing students. The purpose of this quasi-experimental differentiated treatment study was to assess if HPS technology leads to greater clinical decision-making ability and clinical performance compared to the teaching modality of a paper and pencil case study. METHODS: Students (n = 133) learning about the care of a patient with a myocardial infarction at four licensed practical nursing programs (LPN) in Pennysylvania, USA were randomly assigned to one of two groups at each site: an HPS simulation group or a paper and pencil case study group. One-tailed, independent t-tests were used to compare learning gains measured by differences in pre- and postclinical decision-making exam scores and clinical performance. RESULTS: Results indicated that students in the simulation groups were significantly more likely to score higher on the clinical decision-making exams and to respond clinically by performing CPR more quickly on the manikin than students in the case study groups. On the 100-point exam, the simulation groups had a 20-point gain, while the case study groups had a 12-point gain (P < 0.001). Students in the simulation groups provided CPR to a manikin 30 seconds faster, on an average (P < 0.001). DISCUSSION: Results validate the use of HPS technology in nursing education. Ultimately patients may benefit from increased knowledge and speed of care from practical nurses whose training was improved through the use of HPS technology.

The impact of micronutrient supplementation in alcohol-exposed pregnancies on reaction time responses of preschoolers in Ukraine.

The potential of micronutrients to ameliorate the impact of prenatal alcohol exposure (PAE) on attentional regulation skills was explored in a randomized clinical trial conducted in Ukraine. Women who differed in prenatal alcohol use were recruited during pregnancy and assigned to one of three groups [No study-provided supplements, Multivitamin/Mineral Supplement (MVM), or MVM plus Choline]. Their offspring were seen in the preschool period and a reaction time task was administered. Participants were asked to press a response button as quickly as possible as 30 stimuli from the same category (animals) were presented consecutively and then followed by six stimuli from a novel category (vehicles). Number correct, mean latency of the response over trials, and variability in the latency were analyzed separately by sex. During the initial animal trials, boys whose mothers received MVM during pregnancy had more correct responses and reduced response latency compared to boys whose mothers had no MVM treatment. During vehicle trials, maternal choline supplementation was associated with increased response speed in males without a PAE history. Females receiving supplements did not show the same benefits from micronutrient supplementation and were more adversely impacted by prenatal alcohol exposure. Relationships between maternal levels of choline, betaine, and dimethylglycine (DMG) and task performance were also assessed. Although no effects were found for choline after adjusting for multiple comparisons, lower baseline DMG level was associated with greater accuracy and shorter latency of responses in the initial animal trials and shorter latency in the vehicle trials in female preschoolers. Level of betaine in Trimester 3 was associated with reduced variability in the latency of male responses during the animal trials. Maternal micronutrient supplementation in pregnancy appears to improve preschool reaction time performance, but the effects varied as a function of sex and PAE exposure status.

Impact of Age, Frailty, and Dementia on Prescribing for Type 2 Diabetes at Hospital Discharge 2012-2016.

BACKGROUND: The risks of intensive blood glucose lowering may outweigh the benefits in vulnerable older people. OBJECTIVES: Our primary aim was to determine whether age, frailty, or dementia predict discharge treatment types for patients with type 2 diabetes (T2D) and related complications. Secondly, we aimed to determine the association between prior hypoglycemia and discharge treatment types. DESIGN, SETTING AND PARTICIPANTS: We conducted a cohort study involving 3,067 patients aged 65-99 years with T2D and related complications, discharged from Melbourne's Eastern Health Hospital Network between 2012 and 2016. MEASUREMENTS: Multinomial logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CI) for the association between age, frailty, dementia and hypoglycemia, and being prescribed insulin-only, non-insulin glucose-lowering drugs (GLDs) or combined insulin and non-insulin GLDs compared to no GLD. International Classification of Diseases-10 codes were used to identify dementia status and prior hypoglycemia; frailty was quantified using the Hospital Frailty Risk Score. RESULTS: Insulin-only, non-insulin GLDs, combined insulin and non-insulin GLDs, and no GLDs were prescribed to 19%, 39%, 20%, and 23% of patients, respectively. Patients >80 years were less likely than patients aged 65-80 to be prescribed any of the GLD therapies, (eg. non-insulin GLDs [OR 0.67; 95%CI 0.55-0.82]), compared to no GLD. Similarly, high vs. low frailty scores were associated with not being prescribed any of the three GLD therapies, (eg. non-insulin GLDs [OR 0.63; 95%CI 0.45-0.87]). However, dementia was not associated with discharge prescribing of GLD therapies. Patients with a hypoglycemia-related admission were more likely than those not hospitalized with hypoglycemia to receive insulin-only (OR 4.28; 95%CI 2.89-6.31). CONCLUSIONS: Clinicians consider age and frailty when tailoring diabetes treatment regimens for patients discharged from hospital with T2D and related complications. There is scope to optimize prescribing for patients with dementia and for those admitted with hypoglycemia.

Effect of pullet body weight and hen dietary amino acid treatments on their progeny fed high and low amino acid diets.

Four studies were conducted on Cobb 700 broilers to evaluate the dietary protein and any maternal effects on live production and processing parameters. Day-old Cobb 700 broiler breeder pullets were reared to conform to 2 different BW curves (control BW and increased BW) with 8 replicate pens per treatment. Birds were fed common diets from 1 d of age until first egg (24 wk). At 24 wk, 12 pens of each pullet treatment were given different amino acid (AA) diets (low = 14% CP, high = 15% CP). The performance of female and male progeny from 32 and 45 wk hens were evaluated on low AA and high AA density diets. The 4 progeny trial designs were identical factorial 2 × 2 × 2 designs, with 2 pullet BW curves (control BW and increased BW), 2 dam CP diet levels (low and high), and 2 progeny CP diets (low and high), with 6 replicates each containing 18 birds, for a total of 108 broiler progeny per treatment. Broiler chickens on the higher AA density feed exhibited consistent improvement in mid-growth BW and FCR and white meat yield percentage. Some maternal effects were noted, including increased carcass yield in female broilers from 32 wk old hens. There were 3-way interactions of pullet BW × hen dietary AA × progeny dietary AA treatments for female progeny carcass yield (from 32-week-old hens) and male tender yield (from 45-week-old hens). There were 2-way interactions of pullet BW x hen dietary AA treatments effect on female and male progeny drumstick yield from 32-week-old hens, pullet BW × progeny dietary AA treatments effect on male 27 d BW from 32-week-old hens, and hen dietary AA × progeny dietary AA treatments effect on male thigh yield from 45-week-old hen. The epigenetic effects of maternal pullet BW and dietary AA treatments were seen in processing yields suggesting, the need of dietary CP changes of the progeny.

The Mortality After Release from Incarceration Consortium (MARIC): Protocol for a multi-national, individual participant data meta-analysis.

INTRODUCTION: More than 30 million adults are released from incarceration globally each year. Many experience complex physical and mental health problems, and are at markedly increased risk of preventable mortality. Despite this, evidence regarding the global epidemiology of mortality following release from incarceration is insufficient to inform the development of targeted, evidence-based responses. Many previous studies have suffered from inadequate power and poor precision, and even large studies have limited capacity to disaggregate data by specific causes of death, sub-populations or time since release to answer questions of clinical and public health relevance. OBJECTIVES: To comprehensively document the incidence, timing, causes and risk factors for mortality in adults released from prison. METHODS: We created the Mortality After Release from Incarceration Consortium (MARIC), a multi-disciplinary collaboration representing 29 cohorts of adults who have experienced incarceration from 11 countries. Findings across cohorts will be analysed using a two-step, individual participant data meta-analysis methodology. RESULTS: The combined sample includes 1,337,993 individuals (89% male), with 75,795 deaths recorded over 9,191,393 person-years of follow-up. CONCLUSIONS: The consortium represents an important advancement in the field, bringing international attention to this problem. It will provide internationally relevant evidence to guide policymakers and clinicians in reducing preventable deaths in this marginalized population. KEY WORDS: Mortality; incarceration; prison; release; individual participant data meta-analysis; consortium; cohort.

Copper supplementation in quaking mutant mice: reduced tremors and increased brain copper.

Mice homozygous for the mutant gene quaking (qk) with a high frequency of axial tremors had a low concentration of copper in the brain. Supplementation during pregnancy and lactation with a high level of dietary copper greatly reduced the frequency of tremors and brought brain copper level to normal in the off-spring. It is suggested that qk affects copper metabolism.

Communicating risk to emergency department patients with chest pain.

BACKGROUND: The risks and benefits of thrombolytic therapy for acute myocardial infarction are usually discussed with patients before treatment. Numerous factors may make it difficult for a patient to understand these issues fully; one of these is the language doctors use to describe risk. STUDY OBJECTIVE: To determine whether emergency department (ED) patients who experience chest pain have the same understanding of the frequency of side effects when expressed as percentages or in descriptive language (eg, "uncommon") as emergency medicine doctors. SETTING: The chest pain area of an urban ED. METHOD: A short questionnaire survey was administered to both patients and ED doctors. RESULTS: Of the 50 patients recruited, 88% correctly understood data when presented as percentages. When patients were asked to identify the frequency of an "uncommon" and "rare" side effect only 22% and 18%, respectively, were able to do so. The corresponding results for the doctors were 70% (p<0.0001) and 54% (p = 0.0006). 39% of patients felt that there was no difference between these two verbal descriptors. CONCLUSION: Patients understand side-effect frequencies when expressed as percentages. Patients have different understandings of the frequency of events to doctors when verbal descriptors are used. This lack of a shared understanding has implications for informed decision-making and we recommend that percentages are used to communicate risk in the ED.

Implications of altered maternal cytokine concentrations on infant outcomes in children with prenatal alcohol exposure.

Excessive alcohol consumption has been shown to increase serum plasma levels of numerous immune cytokines. Maternal immune activation and elevated cytokines have been implicated in certain neurological disorders (e.g., autism and schizophrenia) in the offspring. We investigated the hypothesis that elevated cytokines during pregnancy are a risk factor in women who gave birth to a child with Fetal Alcohol Spectrum Disorder (FASD) or a child with neurobehavioral impairment, regardless of prenatal alcohol exposure. Moderate to heavy alcohol-exposed (AE) (N = 149) and low or no alcohol-exposed (LNA) (N = 92) women were recruited into the study during mid pregnancy (mean of 19.8 ± 5.8 weeks' gestation) in two regions of Ukraine: Khmelnytsky and Rivne. Maternal blood samples were obtained at enrollment into the study at early to mid-pregnancy and during a third-trimester follow-up visit and analyzed for plasma cytokines. Children were examined at 6 and/or 12 months of age and were classified as having FASD if their mothers reported alcohol use and if they had at least one standardized score (Bayley Scales of Infant Development II Mental Development Index [MDI], or Psychomotor Development Index [PDI]) below 85 with the presence or absence of physical features of FASD. In multivariate analyses of maternal cytokine levels in relation to infant MDI and PDI scores in the entire sample, increases in the ratio of TNF-α/IL-10 and IL-6/IL-10 were negatively associated with PDI scores at 6 months (p = 0.020 and p = 0.036, respectively) and 12 months (p = 0.043 and p = 0.029, respectively), and with MDI scores at 12 months (p = 0.013 and p = 0.050, respectively). A reduction in the odds ratio of having an FASD child was observed with increasing levels of IL-1ß, IL-2, IL-4, IL-6, and IL-10 in early to mid-pregnancy and IL-1ß and IL-10 during late pregnancy. However, women that failed to increase IL-10 levels in the third trimester in order to maintain the balance of pro- and anti-inflammatory cytokines had an elevated risk of having an FASD child, specifically a significant increase in the odds ratio of FASD with every one-unit log increase in late pregnancy TNF-α/IL-10 levels (aOR: 1.654, CI: 1.096-2.495, p = 0.017). These data support the concept that disruptions in the balance between pro- and anti-inflammatory cytokines may contribute to neurobehavioral impairment and alter the risk of FASD.

Biphasic solitary fibrous tumour: a report of two cases with epithelioid features.

We present two cases of solitary fibrous tumour (SFT) showing biphasic morphology with a spectrum of malignant epithelioid components. Slides prepared from formalin-fixed and paraffin-embedded tissue from both cases were stained with haematoxylin and eosin and by immunohistochemistry. Interphase fluorescent in situ hybridisation studies were performed in both cases using paraffin-embedded tissue to look for the t(X;18) translocation, thereby to exclude synovial sarcoma. Both cases showed biphasic morphology with some areas having typical benign spindled SFT morphology (including CD34 expression) and other areas having a malignant epithelioid appearance. In one of the cases, the epithelioid area, which was well circumscribed and showed packeting of cell groups, demonstrated expression of cytokeratin and epithelial cadherin but not of CD34. In the second case, the immunophenotype of the epithelioid component was similar to that of the benign SFT component. These findings suggest that epithelioid change in SFT shows a range of differentiation at one end, similar to that of a standard SFT, and at the other end, possibly acquiring epithelial characteristics.

Evaluation of negative staining technique for determination of CN--insensitive superoxide dismutase activity.

The different forms of superoxide dismutase (superoxide-superoxide oxidoreductase, EC 1.15.11) have been studied, in tissues of rat, mouse and chicken, by the ectrophoresis-nitro blue tetrazolium technique proposed by Beauchamp. Similar enzyme patterns were evident in every tissue. A fast migrating CN--sensitive form of dismutase activity was present in isolated liver mitochondria of each species. Chicken and mouse liver mitochondria, as well as whole homogenate of every tissue of these two species, showed two additional slow-migrating bands of CN--insensitive activity. In contrast, such bands were not detectable in mitochondria isolated from rat liver or in any of the rat tissues analyzed by this technique. Prior to their electrophoretic separation, the samples were analyzed for CN--insensitive superoxide dismutase activity by a spectrophotometric assay; by this assay it was possible to demonstrate and quantitate a CN--insensitive superoxide dismutase activity in every preparation. Two units of CN--insensitive activity were applied to the gels for each sample. These results indicate that the electrophoresis-nitro blue tetrazolium technique is unsuitable for the detection of the rat CN--insensitive form of superoxide dismutase in crude preparations such as whole tissue homogenates or isolated mitochondria.

Folate and homocysteine metabolism in copper-deficient rats.

To investigate the effect of copper deficiency on folate and homocysteine metabolism, we measured plasma, red-cell and hepatic folate, plasma homocysteine and vitamin B-12 concentrations, and hepatic methionine synthase activities in rats. Two groups of male Sprague-Dawley rats were fed semi-purified diets containing either 0. 1 mg (copper-deficient group) or 9.2 mg (control group) of copper per kg. After 6 weeks of dietary treatment, copper deficiency was established as evidenced by markedly decreased plasma and hepatic copper concentrations in rats fed the low-copper diet. Plasma, red-cell, hepatic folate, and plasma vitamin B-12 concentrations were similar in both groups, whereas plasma homocysteine concentrations in the copper-deficient group were significantly higher than in the control group (P<0.05). Copper deficiency resulted in a 21% reduction in hepatic methionine synthase activity as compared to the control group (P<0.01). This change most likely caused the increased hepatic 5-methyltetrahydrofolate and plasma homocysteine concentrations in the copper-deficient group. Our results indicate that hepatic methionine synthase may be a cuproenzyme, and plasma homocysteine concentrations are influenced by copper nutriture in rats. These data support the concept that copper deficiency can be a risk factor for cardiovascular disease.

Influence of maternal dietary Zn intake on expression of diabetes-induced teratogenicity in rats.

Diabetic rat pregnancies are characterized by altered maternal and fetal Zn metabolism and a higher frequency of fetal malformations. In this study, the effect of varying maternal dietary Zn on pregnancy and fetal outcome and on maternal and fetal trace element status were investigated. Starting on day 0 of gestation, streptozocin-induced diabetic and nondiabetic control rats were fed a low-Zn diet (4.5 micrograms/g diet), an adequate-Zn diet (24.5 micrograms/g diet), or a high-Zn diet (500 micrograms/g diet) throughout gestation. Fetuses were taken by cesarean section on gestation day 20. Fetuses from diabetic dams were smaller, weighed less, and had less calcified skeletons and more malformations than fetuses from control dams. In the controls, maternal dietary Zn had a minor effect on fetal malformation frequency. In contrast, in the diabetic animals, the low-Zn diet had a strong teratogenic effect. In diabetic dams, the adequate- and high-Zn diets improved fetal length and weight more than it did in fetuses from nondiabetic dams. However, supplemental dietary Zn during diabetic pregnancy did not further improve malformation frequencies. Liver and kidney Zn, Cu, and metallothionein concentrations were higher in diabetic dams than in control dams. In contrast, liver Zn, Cu, and metallothionein concentrations in fetuses of diabetic dams were lower than in fetuses from control dams, regardless of maternal dietary Zn intake. These results show that diabetes during pregnancy can amplify the teratogenic effects of a mild maternal Zn deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of maternal diabetes on trace element status and fetal development in the rat.

Despite improvements in prenatal care, there is a high incidence of congenital malformations in diabetic pregnancies. Not only is the diabetic patient characterized by a disorder of total fuel metabolism, but abnormal trace element metabolism occurs as well. In the present study, maternal and fetal zinc (Zn), copper (Cu), manganese (Mn), iron (Fe), magnesium (Mg), and calcium (Ca) status has been studied in Sprague-Dawley (SD) and Wistar rats. In addition, the effect of maternal diabetes on fetal development was also investigated. Rats were injected 27 days before mating with streptozocin (STZ, 45 mg/kg) in citrate buffer. On day 20 of gestation, litters were taken by cesarean section. Fetuses from diabetic dams weighed less, and had shorter crown-rump lengths and larger placentas than fetuses from controls. Evaluation of fetal skeletal development revealed fewer calcified sternal sites, anterior phalanges and caudal vertebrae, and an increased frequency of malformations in fetuses of diabetic dams. In dams, diabetics had larger adrenals, kidneys, and liver, and smaller thymus. Abnormal trace element metabolism was evident in diabetic dams and their fetuses. Mn was elevated in maternal liver, kidney and placenta of diabetic animals as well as in fetal liver of pups from diabetic dams. Maternal Cu and Zn levels were also higher in the liver and kidney of diabetic rats. In contrast, fetal liver Zn from fetuses of diabetic mothers was significantly decreased when compared with controls. These results suggest that diabetes may have induced fetal Zn deficiency. If this deficiency is present during embryogenesis/organogenesis, this could be one of the mechanisms of the teratogenicity of the diabetic state.

Combined modality treatment of small cell carcinoma of the lung.

Ninety patients with extensive and 61 with limited small cell carcinoma of the lung were treated with three courses of intravenous chemotherapy (cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate) followed by radiotherapy to intrathoracic disease, and a second three-drug oral combination consisting of lomustine, procarbazine, and methotrexate for one year. Among the 147 patients who were evaluated, 55 of 66 (83%) with limited disease and 53 of 81 (65%) with extensive disease showed response after three courses of chemotherapy. The complete response rate in patients with limited disease prior to radiotherapy was 24%, but increased to 58% when evaluated following radiotherapy. The median survival was 47 weeks for patients with limited disease and 36 weeks for those with extensive disease. A 24% two-year survival is projected for complete responders. Important prognostic factors for survival are performance status, extent of disease, and sex, with female subjects doing somewhat better than male subjects. Among patients with limited disease, 45% failed within the CNS despite the use of chemotherapeutic agents that cross the blood-brain barrier. The initial induction regimen and radiotherapy were well tolerated; the oral three-drug combination was more toxic and did not prevent CNS metastases.

Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus.

OBJECTIVE: To evaluate copper, zinc, manganese, magnesium, and other indices of peroxidative status in diabetic and nondiabetic human subjects. RESEARCH DESIGN AND METHODS: Convenience sample of 57 insulin-dependent or non-insulin-dependent diabetic subjects recruited from the diabetes clinic of the University of California, Davis, Medical Center and 28 nondiabetic subjects recruited from the staffs of the Departments of Internal Medicine and Nutrition. Individuals conducting laboratory analyses were blind to subject group. A fasting blood sample was collected from all subjects and appropriately processed for future analyses. A 24-h urine collection was obtained in a subset of subjects. RESULTS: Hyperzincuria and hypermagnesuria were evident in diabetic subjects compared with control subjects. There were no differences in plasma magnesium or whole-blood manganese between groups. Plasma copper was higher and plasma zinc was lower in diabetic than in control subjects. When data were viewed with respect to specific diabetes-associated complications, diabetic subjects with retinopathy, hypertension, or microvascular disease had higher plasma copper concentrations compared with both diabetic subjects without complications and with control subjects. There were no significant differences between control and diabetic subjects in erythrocyte copper-zinc superoxide dismutase activity or whole-blood glutathione peroxidase or glutathione reductase activities. Plasma peroxide concentrations were higher in diabetic than control subjects. CONCLUSIONS: Diabetes can alter copper, zinc, magnesium, and lipid peroxidation status. Perturbations in mineral metabolism are more pronounced in diabetic populations with specific complications. It is not known whether differences in trace element status are a consequence of diabetes, or alternatively, whether they contribute to the expression of the disease.

Hematologic and trace element alterations following chronic maternal ingestion of propylthiourea.

Rats with diets containing 0.2% propylthiouracil (PTU) throughout gestation had progeny with persistent cyanosis and high neonatal mortality. Histological and histochemical studies failed to reveal lung abnormalities in these pups. Studies of the blood of PTU-fed dams demonstrated that hemoglobin, packed cell volume, and numbers of erythrocytes were significantly reduced. In their 21-day fetal young, erythrocytopenia was accompanied by an elevated mean corpuscular volume and a reduced mean corpuscular hemoglobin concentration. Imprints of marrow from dams and of liver and spleens of the young showed normoblastic erythropoiesis. A granulocytic leucocytosis was present in the blood of the PTU-fed dams, whereas their progeny had a granulocytopenic leucopenia. Tissue concentrations of copper, zinc, manganese, magnesium and iron were determined. The most striking changes observed were the significant elevations of copper in the dams' brain, liver and kidneys. No changes in the concentration of any of the trace minerals were found in the livers of the pups. Food restriction to the dam failed to significantly alter maternal or fetal hematologic or trace element concentrations as compared with controls. It is evident that PTU, when fed to pregnant rats, has demonstrable effects on erythropoiesis, granulocytopoiesis, and maternal trace element distribution. It is not presently known whether these phenomena are interrelated.