Longitudinal metabolite and protein trajectories prior to diabetes mellitus diagnosis in Danish blood donors: a nested case-control study.

AIMS/HYPOTHESIS: Metabolic risk factors and plasma biomarkers for diabetes have previously been shown to change prior to a clinical diabetes diagnosis. However, these markers only cover a small subset of molecular biomarkers linked to the disease. In this study, we aimed to profile a more comprehensive set of molecular biomarkers and explore their temporal association with incident diabetes. METHODS: We performed a targeted analysis of 54 proteins and 171 metabolites and lipoprotein particles measured in three sequential samples spanning up to 11 years of follow-up in 324 individuals with incident diabetes and 359 individuals without diabetes in the Danish Blood Donor Study (DBDS) matched for sex and birth year distribution. We used linear mixed-effects models to identify temporal changes before a diabetes diagnosis, either for any incident diabetes diagnosis or for type 1 and type 2 diabetes mellitus diagnoses specifically. We further performed linear and non-linear feature selection, adding 28 polygenic risk scores to the biomarker pool. We tested the time-to-event prediction gain of the biomarkers with the highest variable importance, compared with selected clinical covariates and plasma glucose. RESULTS: We identified two proteins and 16 metabolites and lipoprotein particles whose levels changed temporally before diabetes diagnosis and for which the estimated marginal means were significant after FDR adjustment. Sixteen of these have not previously been described. Additionally, 75 biomarkers were consistently higher or lower in the years before a diabetes diagnosis. We identified a single temporal biomarker for type 1 diabetes, IL-17A/F, a cytokine that is associated with multiple other autoimmune diseases. Inclusion of 12 biomarkers improved the 10-year prediction of a diabetes diagnosis (i.e. the area under the receiver operating curve increased from 0.79 to 0.84), compared with clinical information and plasma glucose alone. CONCLUSIONS/INTERPRETATION: Systemic molecular changes manifest in plasma several years before a diabetes diagnosis. A particular subset of biomarkers shows distinct, time-dependent patterns, offering potential as predictive markers for diabetes onset. Notably, these biomarkers show shared and distinct patterns between type 1 diabetes and type 2 diabetes. After independent replication, our findings may be used to develop new clinical prediction models.

Identification of blood biomarkers for psychosis using convergent functional genomics.

There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.

Neural tube defects in the Free State province from 2012 to 2016. Is there an increase?

BACKGROUND: Neural tube defects (NTDs) are anomalies of the central nervous system caused by the defective closure of the neural tube during early embryogenesis. A significant decline in the incidence of NTDs after folic acid fortification of food in South Africa was previously shown. Recently, clinical geneticists have voiced concerns that there is a possible resurgence in the number of NTDs. OBJECTIVES: The aim of this study was to determine the incidence of NTDs at a South African Hospital from 2012 to 2016. METHODS: This is a retrospective cross-sectional study where all babies with NTDs born in, or referred to Universitas Hospital were included as study participants. Information was collected for both the mother and the baby from hospital records and data forms. RESULTS: Seventy-seven cases of NTDs were captured from 2012 to 2016. The incidence of NTDs was 0.34/1000 births in the Free State province, and 1.21/1000 births if only the data for babies born in Universitas Hospital and Pelonomi Hospital were used. Further analysis showed a male: female ratio of 1:1. Open spina bifida was the most common defect at 71.4%. CONCLUSION: The incidence of NTDs in the Free State province was low compared to other South African and international studies. The incidence for the metropolitan hospitals is comparable to that of previous studies. This discrepancy is a marker of poor data recording and will impact healthcare planning. A statistically significant increase in NTDs could not be proven.

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

The new medical practice environment. Internists' view of the future.

There have been many changes in the environment in which internal medicine is practiced in recent years. This has been coupled with reports of internists becoming frustrated and of internists leaving primary care practice. We conducted a survey of 219 internists in academic and private practice in western New York. While internists were generally positive regarding the training of residents, there was a pervasive feeling of frustration and demoralization among practicing internists. This demoralization may affect recruitment of new physicians to internal medicine and cause early retirement of practicing internists. The study demonstrated some of the causes of the demoralization.

Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril.

Arthritis and hypertension are frequent comorbidities in the elderly hypertensive population. Nonsteroidal anti-inflammatory drugs are often used to relieve pain in arthritic patients but a side effect is sodium retention and consequent elevation of blood pressure (BP). The effect of dihydropyridine calcium blocking drugs is relatively independent of sodium intake, whereas the angiotensin-converting enzyme (ACE) inhibitors' effects can be blunted by a high-sodium diet. This study compared the effects of indomethacin with placebo in elderly patients with essential hypertension who had been controlled with amlodipine or enalapril. Indomethacin 50 mg twice daily or placebo was administered for 3 weeks in a double-blind crossover study to patients controlled with amlodipine or enalapril. The response was assessed by ambulatory BP measurement. Indomethacin raised BP and lowered pulse rates in patients taking enalapril but had little effect in patients receiving amlodipine. The difference caused by indomethacin between the two groups was 10.1/4.9 mm Hg increase in BP and a 5.6 beats/min fall in pulse in people taking enalapril. Addition of indomethacin to patients taking either drug caused a rise in weight and a fall in plasma renin. It is postulated that the effect is due to inhibition of prostaglandin synthesis, which causes sodium retention. In patients taking amlodipine, the fall in plasma renin ameliorates the effect of sodium retention on BP. In patients taking enalapril, plasma renin falls but this is not translated into an effect because of the blockage of converting enzyme. Thus, the full effect of sodium retention on BP is expressed. In patients treated with indomethacin, fewer patients may respond to ACE inhibitors. However, the major problem is the patient who intermittently takes indomethacin or other nonsteroidal anti-inflammatory drugs, which, if a person is treated by an ACE inhibitor causes BP to go out of control. In such patients amlodipine would appear to be a preferred choice to enalapril.

The role of glutamate and vasopressin in the excitation of RVL neurones by paraventricular neurones.

Neurones in the paraventricular nucleus of the hypothalamus project to rostral ventrolateral medullary spinally projecting vasomotor neurones. We studied the excitatory action and the role of glutamate and vasopressin in this pathway in anaesthetised rats. A five barrel micropipette assembly was used for extracellular recording of neuronal activity and for microiontophoresis of drugs into the vicinity of identified medullary vasomotor neurones. Iontophoresis of L-glutamate or vasopressin into the vicinity of a vasomotor neurone increased activity, effects which were blocked by simultaneous iontophoretic application of a glutamate receptor antagonist, or a vasopressin V(1a) antagonist respectively. Paraventricular neurones were activated either by microinjecting D,L-homocysteic acid or by disinhibition by microinjecting bicuculline. The excitatory effects on vasomotor neurones, of paraventricular nucleus stimulation at some sites were prevented by simultaneous microiontophoretic application of kynurenic acid or at other sites by application of V(1a) antagonist. Neither antagonist altered the ongoing activity of the vasomotor neurones. Therefore, glutamate or vasopressin may act as excitatory neurotransmitters at synapses of paraventricular neurones on rostral ventrolateral medullary vasomotor neurones.

Effect of desipramine on spontaneous arterial pressure oscillations in the rat.

There has been no previous report on the effect of the noradrenaline uptake inhibitor desipramine on short-term variability of arterial pressure. Mean arterial pressure was recorded in 9 conscious resting rats during 4 consecutive 30-min periods: (1) under baseline conditions, (2) after desipramine administration (2 mg/kg i.v., followed by 1 mg/kg every hour), then after (3) cardiac autonomic blockade with methylatropine and atenolol, and (4) alpha-adrenoceptor blockade with phentolamine. Fast Fourier transform analysis was applied to beat-to-beat data after resampling at 10 Hz of consecutive 205-s time series. Desipramine did not change the mean level and overall variability of mean arterial pressure. However, spectral power in the mid-frequency (0.3-0.5 Hz) band containing the Mayer waves was reduced by more than 80%, and power in the low-frequency (0.05-0.2 Hz) band was enhanced by approximately 50%, especially due to the appearance of a major oscillation centred at 0.095 +/- 0.005 Hz. This slow oscillation was further enhanced after cardiac autonomic blockade and was abolished after alpha-adrenoceptor blockade. In conclusion, desipramine profoundly alters short-term arterial pressure variability in resting rats, mainly by shifting vasomotor waves from 0.4 to 0.1 Hz. Desipramine may prove a valuable pharmacological tool to study the dynamic aspects of arterial pressure control.

Experimental parasitization of eggs of Triatoma maculata (Erichson) by the oriental microhymenopteran, Gryon triatomae Masner and comment on the susceptibility of other neotropical triatomines.

The oriental microhymenopteran wasp, Gryon triatomae Masner, 1975 was reared in eggs of triatomine bugs, including vectors of Chagas' disease. In particular, G. triatomae was maintained for 31 generations in eggs of Triatoma maculata (Erichson). Only one parasite develops in each bug egg and 30 to 40 days are required for completion of development at 24 +/- 1 degrees C. Mean parasitization rate of 7484 eggs of T. maculata, in 54 rearings, was 34.7% with a range from zero to the highest rate of 86.7%. Mated females produce predominantly female progeny (mean sex ratio, 1 male:6.7 females). Unmated females produce parthenogenetic males. The wasp reproduces in fertile eggs, from those recently laid to those with well-advanced bug embryos. Infertile eggs are not usually parasitized. Both sexes survive for one to two weeks unfed, but for several weeks (up to 16 for females) if fed (on honey). Frequent ovipositions may reduce survival. Successful parasitization by females persisted for about three weeks but declined subsequently. Abortions of developing Gryon were usually 10% or less. Brief comparison with other neotropical triatomine species indicates that eggs of Triatoma spp. are susceptible to G. triatomae; Panstrongylus spp. seem relatively poor hosts, and there is little or no parasitization of Rhodnius spp.

Parasitization by the microhymenopteran Gryon triatomae Masner of eggs of Triatoma maculata (Erichson) in holes and mazes of artificial walls.

Oriental parasitoid wasps, Gryon triatomae, were confined for several weeks in transparent tanks (400 X 180 X 200 mm) with eggs of the neotropical triatomine bug Triatoma maculata. The eggs were lodged in moulded holes (about 50 mm deep and 15 mm diameter) of polystyrene blocks, to simulate walls. The blocks were arranged with the holes either vertical or horizontal; openings of the holes were either 5 mm or 15 mm diameter. One wall included three mazes of linked holes, each maze with one entrance. Eggs were also accessible in an open petri-dish and on top of one wall. Some eggs in the walls and the maze block were in holes sealed off from access by wasps to provide controls, in order to assess fertility of the eggs, since this favours parasitization. This was satisfactory at 82.2% and 88.5% in two tanks studied. Parasitization rates were 32% of 50 eggs exposed to one female G. triatomae, with one male wasp, in one tank, and in the other 55.9% of 136 eggs exposed to 14 female wasps, with five males. In both tanks, eggs in the open petri-dish, in accessible vertical and horizontal holes and on top of walls were parasitized, but parasitization of eggs in the mazes occurred only in the tank with 14 female Gryon and then as far as the last, 18th, hole of the longest maze, a linear penetration by a searching wasp of about 270 mm; the distance travelled could be considerably greater. Late wasp oviposition after protracted questing may have caused the observed 15.8% abortion rate of G. triatomae. The few wasps seen by night were at rest, but at daybreak many more emerged from the walls and flew actively.(ABSTRACT TRUNCATED AT 250 WORDS)

Limits of clinical tests to screen autonomic function in diabetes type 1.

OBJECTIVES: A precocious detection of cardiac autonomic dysfunction is of major clinical interest that could lead to a more intensive supervision of diabetic patients. However, classical clinical exploration of cardiac autonomic function is not easy to undertake in a reproducible way. Thus, respective interests of autonomic nervous parameters provided by both clinical tests and computerized analysis of resting blood pressure were checked in type 1 diabetic patients without orthostatic hypotension and microalbuminuria. MATERIAL AND METHODS: Thirteen diabetic subjects matched for age and gender to thirteen healthy subjects volunteered to participate to the study. From clinical tests (standing up, deep breathing, Valsalva maneuver, handgrip test), autonomic function was scored according to Ewing's methodology. Analysis of resting beat to beat blood pressure provided autonomic indices of the cardiac function (spectral analysis or Z analysis). RESULTS: 5 of the 13 diabetic patients exhibited a pathological score (more than one pathological response) suggesting the presence of cardiovascular autonomic dysfunction. The most discriminative test was the deep breathing test. However, spectral indices of BP recordings and baro-reflex sensitivity (BRS) of these 5 subjects were similar to those of healthy subjects and of remaining diabetic subjects. CONCLUSION: Alteration in Ewing's score given by clinical tests may not reflect an alteration of cardiac autonomic function in asymptomatic type 1 diabetic patients, because spectral indices of sympathetic and parasympathetic (including BRS) function were within normal range. Our results strongly suggest to confront results provided by both methodologies before concluding to an autonomic cardiac impairment in asymptomatic diabetic patients.

Predictors of young physicians practicing specialties without prior graduate medical education.

OBJECTIVE: This study identifies predictors of young physicians practicing specialties for which they did not report having graduate medical education. DATA SOURCE: A secondary analysis was conducted using a nationally representative survey of young physicians, Practice Patterns of Young Physicians, 1987 (United States). Physicians were under 40 years of age and in uninterrupted practice more than one but fewer than six complete years. STUDY DESIGN: Young physicians who practiced specialties without prior graduate medical education (GME) in these specialties were compared to young physicians who practiced only the specialties for which they reported GME. Comparisons were made on sociodemographic characteristics, international medical graduate status, number and types of GME specialties, year completed GME, and preference for a practice position that was not offered. DATA EXTRACTION METHODS: Sample size was 4,440, including 345 (7.8 percent) physicians who practiced specialties without prior GME. Logistic regression analysis was used to identify predictors of young physicians practicing specialties without prior GME. PRINCIPAL FINDINGS: Physicians who practiced specialties without prior GME more likely were younger, members of minorities other than Black, and with a physician father, high medical school educational debt, and GME in the more generalist specialties. Interaction effects occurred among sex, marital status, and having had GME in internal medicine. Goodness-of-fit analyses indicated that the predictors were useful, but classification table results indicated that at best two out of three cases could be correctly classified. CONCLUSIONS: Practicing specialties without prior graduate medical education in those specialties was related to sociodemographic characteristics and type of specialty training, but a fuller understanding of the circumstances affecting physician specialty changes will require querying physicians directly about their practice choices.

Implementation of an inpatient case management program in rural hospitals.

The objective of the study was to identify factors that affected the implementation of an inpatient case management program in rural hospitals. The hospitals studied were from the Western New York Rural Health Care Cooperative. Five of the hospitals implemented the program in 1992. A qualitative evaluation was conducted by analyzing tape-recorded interviews with nurses and chief executive officers to identify obstacles to and facilitators of program implementation. Many obstacles to implementation could be traced to workload and time constraints, physician autonomy concerns, and limited nursing staff and physician participation. Implementation was facilitated foremost by the effort and supportive attitudes of nursing leaders and hospital chief executive officers. This study concluded that it should be possible to successfully implement conceptually sound managed care and case management programs in rural hospitals, but it will require a relatively long period of support, especially from hospital administration and nursing leaders.

Culture shock in a university health service: a case and commentaries.

The detailed experience of one international student provides a case history in the use of college health services. His journey through the campus health center and outside referrals reveals important facets of student healthcare. It also offers some insights into foreign students' feelings as they contrast their health encounters with expectations carried from home. Four commentaries on the case attempt to draw inferences and to explain from various points of view what the student found in the course of seeking a diagnosis for rectal bleeding.

Working through a psychotherapy group's political cultures.

Macropolitical evolution, starting with authoritarian monarchism, has moved through anarchistic transitions either to the totalitarianism of fascism and communism or to liberal and social democracy. We posit analogous micropolitical development in process-oriented therapy groups: "dependence" and "counterdependence" corresponding to monarchism and anarchism; and "independence" and "interdependence" to liberal and social democracy, respectively. Transition from counterdependence to independence and interdependence may be: (1) facilitated through group members' cooperative experience of rebellion, or (2) blocked by collective identification, the internalization of dystopian or utopian fantasies that coalesce as "group-self" perceptions. We explore how group therapists work clinically with and through these several "political cultures" in the service of group and self transformation.

On scapegoating in therapy groups: a social constructivist and intersubjective outlook.

The social constructs of the group, the group self of an individual member, and the moral order of the group as a whole are described as basic, interrelated concepts essential to our understanding of scapegoating. Two patterns of scapegoating are then introduced: one concerns antagonistic, the other, agonistic relations of scapegoat to scapegoaters. A series of case examples are presented, one involves an advocacy group of socio-cultural "outsiders;" the other three pertain to scapegoating in therapy group settings. The case materials illustrate the meaning and usefulness of an intersubjective/social constructivist perspective on the problem of scapegoating.

[Pediatric drug development: ICH harmonized tripartite guideline E11 within the United States of America, the European Union, and Japan]. / ICH E11 : développement d'un médicament pédiatrique : comparaison entre les États-Unis, l'Union Européenne et le Japon.

To address the lack of appropriate pediatric drugs available on the global market, in 2000 the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued the ICH E11 guideline regarding the Clinical Investigation of Medicinal Products in the Pediatric Population. This guideline considerably changes the environment of drug development for children. It has been written specifically to harmonize, promote, and facilitate high-quality and ethical clinical research for children within the ICH regions, i.e., the United States of America (USA), the European Union (EU), and Japan. This article details the various regulations applicable in each ICH region following the publication of the guideline. The framework of rewards, incentives, and obligations for pharmaceutical companies established for the development of pediatric drugs are compared. It appears that the USA and the EU have both developed specific regulations for pediatric drug development while Japan has not. However, in Japan, pharmaceutical companies (PCs) are encouraged to develop pediatric drugs voluntarily, and they may be granted additional months of market exclusivity or the postponement of the drug re-examination deadline. In both the USA and the EU, regulations aimed to increase the number of clinical studies conducted in children, in order to ensure that the necessary data are generated, determining the conditions in which a drug may be authorized to treat the pediatric population. PCs are encouraged to develop pediatric assessment, including pediatric clinical trials, which is described in a pediatric plan submitted to the relevant authorities. A system of rewards for PCs submitting an application for marketing authorization containing pediatric use information has been put in place to cover the additional investment for testing drugs in children. Subject to conditions, these rewards consist in a 6-month extension of the patent or supplementary protection. Regarding the approval for new medicinal products in these two regions, regulations require PCs to include, when it is relevant, a pediatric assessment in their drug research and development plan, which must be approved. Although these regions have implemented the ICH guideline, the regulation differs with respect to the timing of studies in children relative to adults and approval of a pediatric drug development plan. Except for special cases, the pediatric investigation plan in the EU is required to be prepared and submitted to the competent authorities upon availability of adult pharmacokinetic studies (after phase I), which means at an early phase of a new drug development plan. In the USA, the pediatric plan is requested later during the phase II or III trials. In practice, it has become difficult for pharmaceutical industries to develop a practicable clinical program for pediatrics including timelines for studies in children that satisfy both EU and USA authorities. Nevertheless, at an early stage of the development strategy, direct support and advice from competent authorities can be obtained. For the ICH regions, pediatric committees are well-established albeit less structured in Japan. Their roles are to review and assess pediatric plans, to issue recommendations, to advise pharmaceutical companies on the content and format of pediatric data to be methodically collected and analyzed, and to avoid exposing children to unnecessary or redundant clinical trials. This regulatory framework encourages the study and the development of pediatric drugs, but it is still quite difficult to actually measure the impact of the ICH E11 on increasing the number of drugs for pediatric use.

Plastic ingestion in marine-associated bird species from the eastern North Pacific.

In addition to monitoring trends in plastic pollution, multi-species surveys are needed to fully understand the pervasiveness of plastic ingestion. We examined the stomach contents of 20 bird species collected from the coastal waters of the eastern North Pacific, a region known to have high levels of plastic pollution. We observed no evidence of plastic ingestion in Rhinoceros Auklet, Marbled Murrelet, Ancient Murrelet or Pigeon Guillemot, and low levels in Common Murre (2.7% incidence rate). Small sample sizes limit our ability to draw conclusions about population level trends for the remaining fifteen species, though evidence of plastic ingestion was found in Glaucous-Winged Gull and Sooty Shearwater. Documenting levels of plastic ingestion in a wide array of species is necessary to gain a comprehensive understanding about the impacts of plastic pollution. We propose that those working with bird carcasses follow standard protocols to assess the levels of plastic ingestion whenever possible.