Maternal Starvation Research Articles

The Impact of Hyperemesis Gravidarum on Fetal Development and Birth Outcomes: A Systematic Review and Meta-Analysis

Background: Hyperemesis gravidarum (HG) is a condition characterized by severe nausea and vomiting experienced during pregnancy, with an incidence rate estimated to affect between 0.3% and 2% of pregnant individuals. As HG results in prolonged periods of maternal starvation and multiple nutritional deficiencies, it can potentially disrupt the delicate balance of nutrients and metabolic processes required for optimal fetal growth and development. This systematic review aims to analyze the impact of HG on fetal development and birth outcomes. Methods: The following databases were searched from January 2000 to March 2024: PubMed, Web of Science, Science Direct, Medline (Ovid), and Embase (Ovid). The search focused on HG and its pathogenesis, treatment, fetal development, and pregnancy-related adverse outcomes. Results: 6 out of 907 studies were included which focused on HG with fetal development and birth outcomes. All 6 studies were cohort studies and the quality was high. Meta-analysis revealed that HG is associated with an increased risk of preterm birth (odds ratio (OR): 1.2; 95% confidence interval (95% CI): 1.17–1.23) and small for gestational age (SGA) (OR: 1.30; 95% CI: 1.22–1.40). Conclusions: A limited number of studies have investigated the effects of HG on fetal development and birth outcomes. The present systematic review indicated an increased risk of preterm birth and SGA associated with HG; however, high heterogeneity among the limited included studies should be noted.

Nutrient deprivation induces mouse embryonic diapause mediated by Gator1 and Tsc2.

Embryonic diapause is a special reproductive phenomenon in mammals that helps embryos to survive various harsh stresses. However, the mechanisms of embryonic diapause induced by the maternal environment is still unclear. Here, we uncovered that nutrient deficiency in uterine fluid was essential for the induction of mouse embryonic diapause, shown by a decreased concentration of arginine, leucine, isoleucine, lysine, glucose and lactate in the uterine fluid of mice suffering from maternal starvation or ovariectomy. Moreover, mouse blastocysts cultured in a medium with reduced levels of these six components could mimic diapaused blastocysts. Our mechanistic study indicated that amino acid starvation-dependent Gator1 activation and carbohydrate starvation-dependent Tsc2 activation inhibited mTORC1, leading to induction of embryonic diapause. Our study elucidates the essential environmental factors in diapause induction.

A case series of euglycemic starvation ketoacidosis in pregnant women with COVID-19 infection: atypical presentations

Background: We present a case series of euglycemic starvation ketoacidosis in pregnant women with coronavirus disease 2019 (COVID-19) infection. Our patients presented with fever and typical respiratory symptoms secondary to COVID-19 infection in the third trimester. It was complicated by severe metabolic ketoacidosis, likely contributed by the hypermetabolic state of pregnancy, maternal starvation, and increased metabolic demand due to COVID-19 infection. Case Presentation: Among most of the cases, there was a swift resolution of ketoacidosis, through timely fluid resuscitation, dextrose, and insulin. But despite those measures, most of the patients had to undergo emergency cesarean section due to maternal deterioration, preterm delivery, and fetal distress. All the mothers recovered well and were discharged home, but there was one case of neonatal death after preterm delivery. Conclusion: These cases illustrate the importance of early diagnosis of euglycemic ketoacidosis, prompt management, and close monitoring to obviate adverse materno-fetal outcomes in pregnant women with COVID-19 infection.

Fetal programming in diabetes: an emphasis on prevention consequences of ketoacidosis

The article is devoted to the analysis of scientific publications about the negative impact of ketoacidosis in pregnant women with diabetes on the development of the fetal nervous system from the standpoint of fetal programming and finding ways to prevent its negative effects on the fetus. It was found that the index of intellectual development of children 2 years old had a negative correlation with the level of β-hydroxybutyrate in maternal serum in the third trimester of pregnancy. Therefore, there is a need to avoid ketoacidosis and maternal starvation in order to prevent intellectual disabilities.It is known that the control of metabolic processes in mothers with diabetes can affect the autonomic nervous regulation and motor activity of the fetus. To date, there are no studies that have examined the possible relationship between maternal ketone bodies and fetal heart rate variability. Moreover, the routine monitoring of quantitative indicators of ketone bodies is not currently implemented during pregnancy. All existing treatment strategies for diabetes are performed to detect carbohydrate tolerance disorders and correct blood glucose levels with insulin or metformin.Among all the pharmacological methods of preventing the effects of ketosis, of course, the most reasonable and promising is the use of xylitol solutions. Numerous studies have presented that xylitol is an insulin-independent energy source which has a positive effect on carbohydrate and lipid metabolism, helps to correct oxidative stress. Therefore, the study of the state of the fetal autonomic nervous regulation and indicators of intellectual development of the child under the influence of preventing the synthesis of ketone bodies by xylitol infusion may be the basis for improving the management of pregnant women with diabetes.

Prolonged maternal starvation during pregnancy as a factor in the development of diabetes mellitus in a child

Prolonged maternal starvation during pregnancy as a factor in the development of diabetes mellitus in a child

Maternal starvation primes progeny response to nutritional stress

Organisms adapt to environmental changes in order to survive. Mothers exposed to nutritional stresses can induce an adaptive response in their offspring. However, the molecular mechanisms behind such inheritable links are not clear. Here we report that in Drosophila, starvation of mothers primes the progeny against subsequent nutritional stress. We found that RpL10Ab represses TOR pathway activity by genetically interacting with TOR pathway components TSC2 and Rheb. In addition, starved mothers produce offspring with lower levels of RpL10Ab in the germline, which results in higher TOR pathway activity, conferring greater resistance to starvation-induced oocyte loss. The RpL10Ab locus encodes for the RpL10Ab mRNA and a stable intronic sequence RNA (sisR-8), which collectively repress RpL10Ab pre-mRNA splicing in a negative feedback mechanism. During starvation, an increase in maternally deposited RpL10Ab and sisR-8 transcripts leads to the reduction of RpL10Ab expression in the offspring. Our study suggests that the maternally deposited RpL10Ab and sisR-8 transcripts trigger a negative feedback loop that mediates intergenerational adaptation to nutritional stress as a starvation response.

Metabolic Ketoacidosis in a Gravida Diagnosed with COVID-19: A Case Report

We present a case of term pregnancy which presented with chief complaint of Breathlessness, chest pain as well as a one day history of vomiting. She tested positive for COVID19 through reverse transcriptase polymerase chain reaction of nasopharyngeal swab and the symptoms were attributed to Pneumonia caused due to COVID19.However,the arterial blood gas showed metabolic acidosis with high anion gap. This was a non lactate acidosis with no hypoxemia. Most reasonably the state of pregnancy with increased energy demands along with increased metabolic maternal demand due to infection coupled with maternal starvation had resulted in this Ketoacidosis . In view of non progression of labor caesarian section was carried out and a healthy neonate was delivered. There was an initial improvement in maternal ketoacidosis post partum however optimal management of COVID19 pneumonia required oxygen support and use of corticosteroids. Thus we highlight how an unusual metabolic demands of pregnancy might mimic COVID 19.

Maternal stress suppresses cell proliferation in the forebrain of zebrafish larvae.

Exposure to early life stress (ELS) can increase vulnerability to various psychiatric disorders. Although ELS has been shown to alter structure and functions of the hippocampus, amygdala and prefrontal cortex in the adult mammalian brain, it remains largely unclear whether ELS also affects embryonic or early-stage brain development. In this study, I investigated the effects of a maternal stress (maternal starvation for 4days) of adult zebrafish on offspring's larval brain development. Although maternal starvation did not largely affect proliferation rate in the midbrain and hindbrain, it significantly decreased that in the forebrain of larvae at 5days post-fertilization (dpf). I also found that embryos at 10hr post-fertilization (hpf) born from a starved mother showed elevated cortisol levels compared to those born from a control mother. Furthermore, cortisol treatment was sufficient to decrease proliferating cells in the forebrain of 5dpf larvae. Our findings thus demonstrate for the first time that maternal starvation induces neurodevelopmental changes in the forebrain of zebrafish larvae and points to a possible role of maternal cortisol in mediating this effect of maternal stress to offsprings.

P38-Mitogen Activated Kinases Mediate a Developmental Regulatory Response to Amino Acid Depletion and Associated Oxidative Stress in Mouse Blastocyst Embryos.

Maternal starvation coincident with preimplantation development has profound consequences for placental-fetal development, with various identified pathologies persisting/manifest in adulthood; the ‘Developmental Origin of Health and Disease’ (DOHaD) hypothesis/model. Despite evidence describing DOHaD-related incidence, supporting mechanistic and molecular data relating to preimplantation embryos themselves are comparatively meager. We recently identified the classically recognized stress-related p38-mitogen activated kinases (p38-MAPK) as regulating formation of the extraembryonic primitive endoderm (PrE) lineage within mouse blastocyst inner cell mass (ICM). Thus, we wanted to assay if PrE differentiation is sensitive to amino acid availability, in a manner regulated by p38-MAPK. Although blastocysts appropriately mature, without developmental/morphological or cell fate defects, irrespective of amino acid supplementation status, we found the extent of p38-MAPK inhibition induced phenotypes was more severe in the absence of amino acid supplementation. Specifically, both PrE and epiblast (EPI) ICM progenitor populations remained unspecified and there were fewer cells and smaller blastocyst cavities. Such phenotypes could be ameliorated, to resemble those observed in groups supplemented with amino acids, by addition of the anti-oxidant NAC (N-acetyl-cysteine), although PrE differentiation deficits remained. Therefore, p38-MAPK performs a hitherto unrecognized homeostatic early developmental regulatory role (in addition to direct specification of PrE), by buffering blastocyst cell number and ICM cell lineage specification (relating to EPI) in response to amino acid availability, partly by counteracting induced oxidative stress; with clear implications for the DOHaD model.

Starvation stress affects the maternal development and larval fitness in zebrafish (Danio rerio)

The starvation is a common and severe stress for animal survival and development. In aquatic environment, many fish suffer starvation stress in different extent because of the natural migration or feed limitation. When subjected to starved conditions, organisms will employ various adaptive physiological, biochemical, and behavioral changes to regulate metabolism and maintain homeostasis. In the present study, adult female zebrafish were deprived of feed for 1 to 3 weeks to detect the starved effects on adults and larvae. The results showed that biological indexes, RNA/DNA ratios, and nutritional indexes significantly decreased in the female fish after starvation. The number of mature follicles reduced while the average spawning diameter of oocytes increased. For the larvae, the maternal starvation stress distinctly delayed embryonic hatching, decreased larval body length, disrupted larval swimming ability, and reduced survival rate at early-life stages. Furthermore, we found that DNA methylation might conduce to the downregulated mRNA expression of anti-Müllerian hormone and cytochrome P450 aromatase in retarded ovaries under starved conditions. Significant effects on autophagic transcription were shown in maternal ovary and larvae responded to starvation stress. Taken together, our study systematically revealed the reproductive impairments of starvation stress and would facilitate the investigation of environmental stress in teleost fish.

Starvation during pregnancy impairs fetal oogenesis and folliculogenesis in offspring in the mouse

Although it is becoming increasingly evident that maternal starvation during pregnancy can have permanent effects on a range of physiological processes in the offspring, scant information is available about the consequence of such condition for oogenesis and hence for lifetime reproductive success of progeny in mammals. In the present study, we address this topic by starving pregnant mice at the time of ovarian differentiation (12.5 days post coitum (dpc)) for three consecutive days and analyzed the consequence first on the survival of the fetal oocytes and their capability to progress throughout the stages of meiotic prophase I (MPI) and then on the postnatal folliculogenesis of the offspring. The results showed that maternal starvation increased apoptosis in the fetal ovaries, resulting in reduction of the oocyte number. Moreover, MPI progression was slowed down in the surviving oocytes and the expression of DNA repair players in the starved ovaries increased. Transcriptome analysis identified 61 differentially expressed genes between control and starved ovaries, the most part of these being involved in metabolic processes. A significant decrease in the percentage of oocytes enclosed in primordial follicles and the expression of oocyte genes critically involved in folliculogenesis such as Nobox, Lhx8 and Sohlh2 in the 3 days post partum (dpp) starved ovaries were found. Finally, at the time of juvenile period (21 dpp), the number of oocytes and antral follicles resulted significantly lower in the ovaries of the offspring from starved mothers in comparison to controls. Our findings support the notion that maternal starvation can affect ovary development in the offspring that could adversely affect their reproductive success in the adult life.

Association of Gestational Weight Gain and Maternal Body Mass Index in Early Pregnancy With Risk for Nonaffective Psychosis in Offspring

Prenatal exposure to famine is associated with a 2-fold risk for nonaffective psychoses. Less is known about whether maternal nutrition states during pregnancy modify offspring risk for nonaffective psychoses in offspring in well-fed populations. To determine whether gestational weight gain (GWG) during pregnancy and maternal body mass index (BMI) in early pregnancy are associated with risk for nonaffective psychoses in offspring. This population-based cohort study used data from Swedish health and population registers to follow up 526 042 individuals born from January 1, 1982, through December 31, 1989, from 13 years of age until December 31, 2011. Cox proportional hazards regression models adjusted for socioeconomic status and potential risk factors were used to examine the risk for developing nonaffective psychoses. Family-based study designs were used to further test causality. Data were analyzed from February 1 to May 14, 2016. Gestational weight gain during pregnancy, maternal body mass index at the first antenatal visit, and paternal body mass index at the time of conscription into the Swedish military (at 18 years of age). Hazard ratios (HRs) for the diagnosis of nonaffective psychoses (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes F20 to F29 and International Classification of Diseases, Ninth Revision [ICD-9] codes 295, 297 and 298, except 298A and 298B) and narrowly defined schizophrenia (ICD-9 code 295 and ICD-10 code F20). The 526 042 individuals in the cohort (48.52% female and 51.47% male; mean [SD] age, 26 [2.3] years) included 2910 persons with nonaffective psychoses at the end of follow-up, of whom 704 had narrowly defined schizophrenia. Among the persons with nonaffective psychosis, 184 (6.32%) had mothers with extremely inadequate GWG (<8 kg for mothers with normal baseline BMI), compared with 23 627 (4.52%) of unaffected individuals. Extremely inadequate GWG was associated with an increased risk for nonaffective psychoses among offspring in adjusted models (HR, 1.32; 95% CI, 1.13-1.54) and in matched-sibling analysis (HR, 1.61; 95% CI, 1.02-2.56). Similar patterns were observed when considering narrowly defined schizophrenia as the outcome. Maternal mild thinness in early pregnancy was weakly associated with an increased risk for nonaffective psychosis in offspring (HR for BMI≥17.0 and <18.5, 1.21; 95% CI, 1.01-1.45), as was paternal severe thinness (HR for BMI<16.0, 2.53; 95% CI, 1.26-5.07) in mutually adjusted models. In matched-sibling analysis, no association was observed between maternal underweight (HR, 1.46; 95% CI, 0.90-2.35), overweight (HR, 1.11; 95% CI, 0.73-1.68), or obesity (HR, 0.56; 95% CI, 0.23-1.38) and risk for nonaffective psychosis in offspring. Inadequate GWG was associated with an increased risk for nonaffective psychosis in offspring, consistent with historical studies on maternal starvation. These findings support the role of maternal undernutrition in nonaffective psychosis pathogenesis.

Neurodegenerative aspects in vulnerability to schizophrenia spectrum disorders.

The neurodegenerative and neurotoxic aspects of schizophrenia and/or psychosis involve genetic, epigenetic, and neurotoxic propensities that impinge upon both the symptom domains and the biomarkers of the disorder, involving cellular apoptosis/excitotoxicity, increased reactive oxygen species formation, viral and bacterial infections, anoxic birth injury, maternal starvation, drugs of abuse, particularly cannabis, metabolic accidents, and other chemical agents that disrupt normal brain development or the integrity of brain tissues. Evidence for premorbid and prodromal psychotic phases, aspects of neuroimaging, dopamine, and psychosis vulnerability, and perinatal aspects provide substance for neurodegenerative influences. Not least, the agencies of antipsychotic contribute to the destructive spiral that disrupts normal structure and function. The etiopathogenesis of psychosis is distinguished also by disruptions of the normal functioning of the neurotrophins, in particular brain-derived neurotrophic factor, dyskinesic aspects, immune system disturbances, and metabolic aspects. Whether detrimental to neurodevelopment or tissue-destructive, or an acceleration of neurotoxic pathways, the notion of neurodegeneration in the pathophysiology of schizophrenia spectrum and psychotic disorders continues to gather momentum.

Relationship of Maternal Malnutrition Caused by Di(2-ethylhexyl) Phthalate Exposure with Lifestyle Disease in Offspring

The hypothesis that offspring growing up malnourished during their fetal period have a high risk of lifestyle diseases in later life has been attracting great attention. Although animal experiments and epidemiological studies have been reported, most of them focused on the deficiency of maternal malnutritional elements or starvation. We found that di(2-ethylhexyl) phthalate (DEHP) decreased maternal plasma triglyceride levels, which is a significant source of nutrients for fetuses, in mice. Therefore, we analyzed how offspring exposed to malnutritional status during their fetal period develop potential adverse effects in later life. Male and female wild-type (mPPARα), Pparα-null, and hPPARα mice were treated with diets containing 0 or 0.05% DEHP. After 4 weeks, males and females in the same genotype and dose group were mated. After continued exposure until weaning, each group was divided into two groups, and one of them was dissected. The remaining was further divided into two subgroups; one was fed normal feed (control-diet group), while the other was fed a high-fat diet (HFD group). After 8-week feeding, all the mice were dissected. In the control-diet group, DEHP exposure at the fetal and pup stages increased food consumption in mPPARα and hPPARα mice, but not in Ppara-null mice. In contrast, DEHP exposure decreased plasma leptin levels in mPPARα and hPPARα mice at the weaning stage. In the HFD group, DEHP exposure at the fetal and pup stages influenced neither food consumption nor leptin levels. These findings suggest that maternal malnutrition may be caused by not only nutritional deficiency but also exposure to some chemicals such as DEHP, and the latter case may also influence feeding behavior in offspring. These effects may be related to hepatic PPARα and diminished by HFD feeding. Further study is warranted as to whether such feeding behavior influences the risk of lifestyle diseases such as obesity.

The Imprinted Brain: How Genes Set the Balance Between Autism and Psychosis

The imprinted brain theory proposes that autism spectrum disorder (ASD) represents a paternal bias in the expression of imprinted genes. This is reflected in a preference for mechanistic cognition and in the corresponding mentalistic deficits symptomatic of ASD. Psychotic spectrum disorder (PSD) would correspondingly result from an imbalance in favor of maternal and/or X-chromosome gene expression. If differences in gene expression were reflected locally in the human brain as mouse models and other evidence suggests they are, ASD would represent not so much an 'extreme male brain' as an extreme paternal one, with PSD correspondingly representing an extreme maternal brain. To the extent that copy number variation resembles imprinting and aneuploidy in nullifying or multiplying the expression of particular genes, it has been found to conform to the diametric model of mental illness peculiar to the imprinted brain theory. The fact that nongenetic factors such as nutrition in pregnancy can mimic and/or interact with imprinted gene expression suggests that the theory might even be able to explain the notable effect of maternal starvation on the risk of PSD - not to mention the 'autism epidemic' of modern affluent societies. Finally, the theory suggests that normality represents balanced cognition, and that genius is an extraordinary extension of cognitive configuration in both mentalistic and mechanistic directions. Were it to be proven correct, the imprinted brain theory would represent one of the biggest single advances in our understanding of the mind and of mental illness that has ever taken place, and would revolutionize psychiatric diagnosis, prevention and treatment - not to mention our understanding of epigenomics.

Maternal investment, sibling competition, and offspring survival with increasing litter size and parity in pigs (Sus scrofa)

The aim of this study was to examine the effects of litter size and parity on sibling competition, piglet survival, and weight gain. It was predicted that competition for teats would increase with increasing litter size, resulting in a higher mortality due to maternal infanticide (i.e., crushing) and starvation, thus keeping the number of surviving piglets constant. We predicted negative effects on weight gain with increasing litter size. Based on maternal investment theory, we also predicted that piglet mortality would be higher for litters born late in a sow's life and thus that the number of surviving piglets would be higher in early litters. As predicted, piglet mortality increased with increasing litter size both due to an increased proportion of crushed piglets, where most of them failed in the teat competition, and due to starvation caused by increased sibling competition, resulting in a constant number of survivors. Piglet weight at day 1 and growth until weaning also declined with increasing litter size. Sows in parity four had higher piglet mortality due to starvation, but the number of surviving piglets was not affected by parity. In conclusion, piglet mortality caused by maternal crushing of piglets, many of which had no teat success, and starvation caused by sibling competition, increased with increasing litter size for most sow parities. The constant number of surviving piglets at the time of weaning suggests that 10 to 11 piglets could be close to the upper limit that the domestic sow is capable of taking care of.

The failure of the schizophrenia concept and the argument for its replacement by hebephrenia: applying the medical model for disease recognition

The failure of the schizophrenia concept and the argument for its replacement by hebephrenia: applying the medical model for disease recognition

Thioredoxin Binding Protein-2 Inhibits Excessive Fetal Hypoglycemia During Maternal Starvation by Suppressing Insulin Secretion in Mice

Glucose is a major fuel for fetal development. Fetal blood glucose level is mainly dependent on maternal blood glucose concentration, though it is also regulated by fetal insulin level. Thioredoxin binding protein-2 (TBP-2), which is identical to vitamin D3 up-regulated protein (VDUP1) and thioredoxin interacting protein (Txnip), was recently reported to be a key transcriptional factor controlling glucose metabolism. Here, we elucidated the functions of TBP-2 in maintaining blood glucose homeostasis during the fetal period. TBP-2(+/-) female mice were mated with TBP-2(+/-) male mice; beginning 16.5-d post coitum, pregnant mice were fed or fasted for 24 h. Under conditions of maternal starvation, the blood glucose levels of TBP-2(-/-) fetuses were significantly lower than those of TBP-2(+/+) fetuses, corresponding to the elevated plasma insulin levels of TBP-2(-/-) fetuses compared with those of TBP-2(+/+) fetuses. There was no difference between TBP-2(+/+) and TBP-2(-/-) fetuses in terms of their pancreatic beta-cell masses or the expression of placental glucose transporters under conditions of either maternal feeding or fasting. Thus, during maternal fasting, fetal TBP-2 suppresses excessive insulin secretion to maintain the fetus's glucose levels, implying that TBP-2 is a critical molecule in mediating fetal glucose homeostasis depending on nutrient availability.

Hepatic Glycogen Synthesis in the Absence of Glucokinase: THE CASE OF EMBRYONIC LIVER

Glucokinase (GK, hexokinase type IV) is required for the accumulation of glycogen in adult liver and hepatoma cells. Paradoxically, mammalian embryonic livers store glycogen successfully in the absence of GK. Here we address how mammalian embryonic livers, but not adult livers or hepatoma cells, manage to accumulate glycogen in the absence of this enzyme. Hexokinase type I or II (HKI, HKII) substitutes for GK in hepatomas and in embryonic livers. We engineered FTO2B cells, a hepatoma cell line in which GK is not expressed, to unveil the modifications required to allow them to accumulate glycogen. In the light of these results, we then examined glycogen metabolism in embryonic liver. Glycogen accumulation in FTO2B cells can be triggered through elevated expression of HKI or either of the protein phosphatase 1 regulatory subunits, namely PTG or G L. Between these two strategies to activate glycogen deposition in the absence of GK, embryonic livers choose to express massive levels of HKI and HKII. We conclude that although the GK/liver glycogen synthase tandem is ideally suited to store glycogen in liver when blood glucose is high, the substitution of HKI for GK in embryonic livers allows the HKI/liver glycogen synthase tandem to make glycogen independently of the glucose concentration in blood, although it requires huge levels of HK. Moreover, the physiological consequence of the HK isoform switch is that the embryonic liver safeguards its glycogen deposits, required as the main source of energy at birth, from maternal starvation.

New directions in the conceptualization of psychotic disorders

Recent studies raise controversies about the nature of psychotic illnesses, and the role of life experiences and drug abuse as causative agents in the onset of psychoses. Evidence from studies across many geographic locales and cultures finds increased risk of psychoses in first- and second-generation immigrant populations. Trauma incurred in war and civil unrest, trauma of child abuse, and the experience of being bullied in childhood are correlated with increased rates of psychoses in the populations at risk. The risk of onset of psychoses is increased by maternal and infant starvation, and by substance misuse (marijuana, khat) in late childhood and adolescence. These studies question the validity of a categorical distinction between the schizophrenic and affective illnesses. A variety of extrinsic factors, such as in-utero and infant malnutrition, substance abuse, and traumatic experiences, appear to be significant risk factors for the development of schizophrenia-like and psychotic affective disorders. These findings raise the issue of whether the present classification of the psychoses is in urgent need of reconceptualization.