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.

[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.

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.

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.

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.

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.

Inhibitory effects of angiotensin II on barosensitive rostral ventrolateral medulla neurons of the rat.

1. The brain renin-angiotensin system can influence arterial baroreceptor reflex control of blood pressure (BP) through both direct and indirect effects on sympathetic premotor neurons of the rostral ventrolateral medulla (RVLM). The present study examined the direct effect of angiotensin (Ang) II applied by microiontophoresis on the ongoing activity of single RVLM neurons. 2. In 26 urethane-anaesthetized Wistar rats, recordings of single unit activities of barosensitive RVLM neurons were made from one barrel of a six-barrel micropipette assembly. The other five barrels were filled with either L-glutamate, AngII, valsartan (an AT1 receptor antagonist), PD 123177 (an AT2 receptor antagonist) and saline. All drugs were applied by microiontophoresis. 3. Mean BP was 83 +/- 3 mmHg. Application of AngII inhibited the ongoing activity of RVLM neurons, identified as barosensitive because their activity was inhibited by a phenylephrine- induced increase in BP, from 12.6 +/- 1.5 to 5.4 +/- 1.1 Hz (n=24; P < 0.001). Angiotensin II also inhibited the glutamate-evoked excitation of barosensitive RVLM neurons from 15 +/- 3 to 5.8 +/- 2.0 Hz (n=6; P < 0.001). Valsartan significantly increased neuronal activity from 9.5 +/- 2.3 to 13.5 +/- 3.2 Hz (n=7, P < 0.01), whereas PD 123177 significantly decreased neuronal activity from 13.5 +/- 3.5 to 9.9 +/- 2.8 Hz (n=13; P < 0.01). 4. The results suggest that AngII exerts a tonic inhibitory effect on barosensitive RVLM neurons, which is presumably mediated through AT1 receptor stimulation.

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.

Norepinephrine reuptake, baroreflex dynamics, and arterial pressure variability in rats.

This study examined the effect of norepinephrine reuptake blockade with desipramine (DMI) on the spontaneous variability of the simultaneously recorded arterial pressure (AP) and renal sympathetic nerve activity (SNA) in conscious rats. Acute DMI administration (2 mg/kg iv) depressed AP Mayer waves ( approximately 0.4 Hz) and increased low-frequency (<0.2 Hz) components of AP variability. DMI decreased renal SNA variability, especially due to the abolition of oscillations related to Mayer waves. To examine whether DMI-induced changes in AP and renal SNA variabilities could be explained by alterations in the dynamic characteristics of the baroreceptor reflex loop, the frequency responses of mean AP to aortic depressor nerve stimulation were studied in urethan-anesthetized rats. DMI accentuated the low-pass filter properties of the transfer function without significantly altering the fixed time delay. The frequency responses of iliac vascular conductance to stimulation of the lumbar sympathetic chain were studied in an additional group of anesthetized rats. DMI did not markedly alter the low-pass filter properties of the transfer function and slightly increased the fixed time delay. These results suggest that the DMI-induced decrease in the dynamic gain of the baroreceptor reflex is responsible for the decreased spontaneous renal SNA variability and the accompanying increased AP variability. The "slowing down" of baroreflex responses cannot be attributed to an effect of DMI at the vascular neuroeffector junction.

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.

The arterial baroreceptor reflex of the rat exhibits positive feedback properties at the frequency of mayer waves.

1. Modelling studies have led to the proposal that Mayer waves ( approximately 0.4 Hz in rats) could result from a resonance phenomenon in a feedback control loop. In this study, we investigated the presence of a resonance frequency in the arterial baroreceptor reflex loop, i.e. a particular frequency at which arterial pressure feeds back positively to the baroreceptors. 2. Frequency responses of mean arterial pressure (MAP) to aortic depressor nerve (ADN) stimulation were studied in fifteen urethane anaesthetized, ventilated rats with cardiac autonomic blockade. The ADN was stimulated using rectangular trains of impulses (2 ms, 100 Hz) delivered at frequencies ranging from 0.1 to 1 Hz. Phase angles between impulses and MAP were calculated using cross-spectral analysis based on a fast Fourier transform algorithm. 3. Rhythmic ADN stimulation induced regular MAP oscillations at the expected frequencies that were attenuated by alpha-adrenoceptor blockade and abolished after ganglionic blockade. The relationship between impulse and MAP oscillations was characterized by a strong coherence and a positive phase shift at low frequencies, indicating that impulses led MAP with respect to the out-of-phase pattern. Deviation of the phase from the out-of-phase behaviour was mainly due to the presence of a fixed time delay ( approximately 0.8 s) between ADN stimuli and MAP changes. Phase angles fell to zero at 0.42 +/- 0.02 Hz. 4. In rats, the arterial baroreceptor reflex exhibits a resonance frequency close to the frequency of spontaneously occurring Mayer waves. The reflex therefore seems the most likely origin for the Mayer waves.

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.

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.