Socioecological systems analysis of potential factors for cholera outbreaks and assessment of health system's readiness to detect and respond in Ilemela and Nkasi districts, Tanzania.

BACKGROUND: Cholera outbreaks are a recurrent issue in Tanzania, with Ilemela and Nkasi districts being particulary affected. The objective of this study was to conduct a socio-ecological system (SES) analysis of cholera outbreaks in these districts, identifying potential factors and assessing the preparedness for cholera prevention and control. METHODS: A cross-sectional study was carried out in Ilemela and Nkasi districts of Mwanza and Rukwa regions, respectively in Tanzania between September and October 2021. A SES framework analysis was applied to identify potential factors associated with cholera outbreaks and assess the readiness of the districts to cholera prevention and control. RESULTS: Ilemela is characterised by urban and peri-urban ecosystems while Nkasi is mainly rural. Cholera was reported to disproportionately affect people living along the shores of Lake Victoria in Ilemela and Lake Tanganyika in Nkasi, particularly fishermen and women involved infish trading. The main potential factors identified for cholera outbreaks included defecation in the shallow ends and along the edges of lakes, open defecation, bathing/swimming in contaminated waters and improper waste disposal. The preparedness of both districts for cholera prevention and response was found to be inadequate due to limited laboratory capacity, insufficient human resources, and budget constraints. CONCLUSION: People of Ilemela and Nkasi districts remain at significant risk of recurrent cholera outbreaks and the capacity of the districts to detect the disease is limited. Urgent preventive measures, such as conducting considerable community awareness campaigns on personal hygiene and environmental sanitation are needed to alleviate the disease burden and reduce future cholera outbreaks.

Pediatric dental treatments with pharmacological and non-pharmacological interventions: a cross-sectional study.

OBJECTIVES: Behaviour management strategies involving pharmacological or non-pharmacological interventions during dental procedures should be considered to attain safe and successful treatment outcomes. This study compared the frequencies of use and the completeness of treatment with these interventions. METHODS: A total of 1725 dental records of patients up to 18 years old, who were treated in the King Abdulaziz Medical City in Jeddah City from October 2018 to June 2019, were used in this retrospective, cross-sectional study. Inferential analysis, Chi-square test, Kruskal-Wallis test, and regression model were used in the data analysis. RESULTS: About two-thirds of the patients were treated with attendant non-pharmacological interventions, while one-third, with pharmacological interventions. The application of General Anesthesia (GA) was the most frequently used intervention. Restorative procedures and extractions were done in higher frequencies with pharmacological interventions. Treatments with space maintainers and orthodontic appliances were carried out in higher frequencies with non-pharmacological strategies. The choice of intervention was significantly influenced by the systemic conditions of the patients. Patients treated with non-pharmacological intervention comprised the dominant type of patients, because they required treatments with less pain. Those treated with GA needed restorative treatments and extractions, or treatments that involve pain, but these treatments had higher frequencies of being completed. CONCLUSIONS: The treatments with pharmacological intervention through GA have higher frequencies of being completed, compared to those with non-pharmacological interventions. Factors, such as age, potential to complete the treatment, and the type of dental treatment applied, influence the choice of treatment intervention.

Patient with Lynch syndrome with subsequent development of small bowel adenocarcinoma.

Small bowel adenocarcinoma (SBA) is a rare cancer in the general population, but the incidence increases in patients with Lynch syndrome. The present case describes a 57-year-old white woman with a history of colon cancer status posthemicolectomy and diagnosis of Lynch syndrome. Twenty years after her operation, the patient presented with vague abdominal discomfort and constipation, and underwent an exploratory laparotomy which revealed a stage 3A SBA. Genetic testing of the specimen provided evidence of microsatellite instability and faulty DNA repair supporting aetiology of Lynch syndrome. This case is unique in that SBA, if present in patients with Lynch syndrome, is usually a presenting symptom and has not been widely described in literature as an occurrence so many years after. As a result, this case highlights the importance of a low threshold for a thorough evaluation in patients with Lynch syndrome who present with signs of small bowel obstruction.

An 88-year-old woman with flushing, alopecia and hirsutism and a Sertoli-Leydig cell tumour.

Sertoli-Leydig cell tumour (SLCT) is a rare, androgen-secreting sex cord-stromal tumour of the ovary that usually occurs in young premenopausal women. The major clinical manifestations are virilisation and defeminisation. The following case describes an 88-year-old G1P1 woman, 40 years after menopause, who presented with flushing, hirsutism, voice changes and alopecia along with significantly elevated levels of testosterone. Postoperative report revealed a well-differentiated SLCT in the left ovary. This case is unique in that SLCT is a very rare cancer and even more so in an 88-year-old woman. Taking this case into consideration, it becomes reasonable to check androgen and oestrogen levels in postmenopausal women, not only in patients with signs of virilisation, but also in those with non-classical presentations, such as flushing or heat spells.

A Saudi Patient with an Interstitial Deletion of Short Arm of Chromosome 3 (p13 to p21) and its Association with Joubert's Syndrome Features.

We report a case of 4 weeks old girl with a de novo interstitial deletion of the short arm of chromosome 3 (p13-p21) and clinical findings typical of proximal 3p deletion together with heart defects, choanal atresia, ear anomalies, central nervous system anomalies, renal anomalies and associated Joubert's syndrome (JS). Family history is unremarkable and parenteral chromosomes were normal. The clinical manifestations of the patient are compared with those of 11 patients previously described with a proximal 3p deletion. The additional JS features associated with this syndrome were described. This is the first case report in English literature describing 3p deletion associated with additional JS features.

Integrating genomic and epigenomic information: a promising strategy for identifying functional DNA variants of human disease.

In a clinical setting diagnosis, heritability, risk and outcome of human disease rely heavily on the use of markers present in specific tissues. In the past decade, the development of genome-wide, non-hypothesis driven methods to identify molecular markers associated with disease have led to the discovery of numerous genetic variations associated with specific human diseases, the majority of which map within non-coding regions of the genome. In parallel, whole-genome studies focused on the role of gene regulatory epigenetic modifications such as DNA methylation and histone modifications are providing a conceptual framework for understanding the functional significance of sequence variation in human disease. This review highlights selected recent development in epigenetics and discusses their implications with respect to the identification of functional or novel single nucleotide polymorphisms.

Relationship of aldosterone synthase gene (C-344T) and mineralocorticoid receptor (S810L) polymorphisms with gestational hypertension.

The extent of genetic influence in the aetiology of gestational hypertension has not been completely determined. The aim of this study was to analyse the relationship between aldosterone levels and the -344T/C polymorphism of the aldosterone synthase gene (CYP11B2) and to investigate the frequency of the S810L mutation of mineralocorticoid receptor (MR) in gestational hypertension. One hundred women with pregnancy-induced hypertension and 100 with normal pregnancy were studied to measure serum aldosterone and progesterone levels and for the genotypification of the -344T/C polymorphism of CYP11B2 gene and the S810L mutation of MR by RFLP-PCR and SSP, respectively. Serum aldosterone levels were reduced (<0.000001) and serum progesterone levels increased (<0.000001) in gestational hypertensive women as compared with normal pregnant women. The -344T/C of CYP11B2 genotypic frequencies were similar in the hypertensive and normotensive pregnant women. The 810L-mutated allele of MR was found in 12% of the hypertensive and 9.4% of the normotensive pregnant women. In contrast to the observations made in preeclampsia, the genotype of -344T/C of CYP11B2 was neither related with gestational hypertension nor with aldosterone levels at delivery. The frequency of the S810L mutation was similar in the hypertensive and normotensive women but higher than observed in other reports.

Normal size of the lumen of the aorta in dwarf mice lacking IGF-II.

The peptide insulin-like growth factor II (IGF-II) is a foetal promoter of growth and differentiation. Genetically modified mice have provided insights into the contribution of IGF-II to the determination of the size of the body and individual organs. Nevertheless, the role of IGF-II in regulating the size of major blood vessels is poorly understood. Here, the transverse luminal and medial area of the aorta and the number of medial cell nuclei are shown not to be significantly different in adult wild-type and Igf2 nullizygous mice, despite a approximately 30% reduction in BW in the latter group. The observations in this study suggest that IGF-II is not an indispensable factor in the determination of the size of the aortic lumen, and are consistent with the view that growth factor redundancy may be a safeguard mechanism to maintain the size of the aorta within a range compatible with viability.

Increased and persistent circulating insulin-like growth factor II in neonatal transgenic mice suppresses developmental apoptosis in the pancreatic islets.

In rats, a proportion of pancreatic beta-cells are deleted by apoptosis in the second week of postnatal life and replaced by endocrine cell neogenesis from pancreatic ductal epithelium. This coincides with a reduction in pancreatic insulin-like growth factor II (IGF-II) expression, and IGF-II has been shown to act as a beta-cell survival factor in vitro. To examine whether IGF-II regulates beta-cell apoptosis in vivo, an IGF-II transgenic mouse model was used in which mouse IGF-II is overexpressed in skin, gut, and uterus driven by a keratin promoter, so that circulating IGF-II is retained postnatally. Mice were killed between postnatal days 7 and 26, and the pancreas was examined histologically. Apoptotic cells were visualized by the terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling method, and proliferating cells were examined by immunohistochemistry for proliferating cell nuclear antigen. In nontransgenic mice, serum IGF-II was absent by 26 days, but mean (+/-SEM) values were 45+/-9 ng/ml (n = 5) in transgenic animals. A 2- to 3-fold rise in islet cell apoptosis was seen in normal animals between days 11 and 16, but this was substantially decreased in IGF-II transgenic mice (day 11; control, 12+/-1%; transgenic, 6+/-1%; P < 0.01; n = 5). Consequently, islets from IGF-II transgenic mice had a significantly greater mean area from days 11-16, but the proportions of beta- and alpha-cells and circulating insulin levels were not changed. Islet cell DNA synthesis was increased in transgenic mice on days 13 and 16. The total islet number per section did not alter. The results show that a persistent presence of circulating IGF-II postnatally alters endocrine pancreatic ontogeny in the mouse and largely prevents the wave of developmental apoptosis that precipitates beta-cell turnover in neonatal life.

Insulin-like growth factor-2 regulation of conceptus composition: effects of the trophectoderm and inner cell mass genotypes in the mouse.

The purpose of this study was to measure the effect of insulin-like growth factor-2 deficiency on the growth of the mouse conceptus. Initial observations on normal development in the 129J/Sv strain established that wet and dry weights were reduced by 35% when the insulin-like growth factor-2 gene was inactive. The DNA contents were reduced by only 15%. We exchanged the inner cell mass and trophectoderm between mouse blastocysts that had or lacked an active insulin-like growth factor-2 gene. At embryonic Day 16.5, lack of this gene's activity in the derivatives of either tissue decreased the fluid volumes of the exocelomic and amniotic cavities. The wet weights of the "fetal placentas," the yolk sacs, and the fetuses were also decreased. However, the tissue wet weight decrease could not be accounted for by the change in DNA content, indicating that cell-associated biomass had changed. The conclusions are 1) that insulin-like growth factor-2 levels regulate the composition of the fetus and extra-embryonic tissues and 2) that trophectoderm and inner cell mass derivatives cooperate to control extra-cellular fluid volume in the conceptus.

The soluble type 2 insulin-like growth factor (IGF-II) receptor reduces organ size by IGF-II-mediated and IGF-II-independent mechanisms.

The soluble type 2 insulin-like growth factor (IGF) receptor or IGF-II/mannose 6-phosphate receptor (sIGF2R) is produced in vivo by proteolytic deletion of the transmembrane and intracellular domains of the cellular form of the receptor (IGF2R). There is evidence that sIGF2R is a negative regulator of growth. We have shown that transgenic mice expressing an Igf2r cDNA with a deleted transmembrane domain sequence (sDeltaIgf2r) show reduced local organ size. In the present study, we investigate whether sDeltaIGF2R can slow the growth induced by an excess of IGF-II and whether the biological activity of sDeltaIGF2R is due solely to its interactions with IGF-II. To this end, we crossed sDeltaIgf2r transgenics by mice overexpressing IGF-II (Blast line) or by mice carrying a disrupted paternal (active) allele of the Igf2 gene (Igf2(m+/p-)). Analysis of the phenotypes revealed that the soluble IGF2R affects the size of some organs (colon and cecum) exclusively by reducing the biological activity of IGF-II, whereas in other organs (stomach and skin) the biological activity of the receptor is at least in part independent of IGF-II and must involve an interaction with other factor(s).

Local reduction of organ size in transgenic mice expressing a soluble insulin-like growth factor II/mannose-6-phosphate receptor.

Genetic evidence suggests that the insulin-like growth factor II (IGF-II)/mannose-6-phosphate receptor (IGF2R) slows growth. A soluble form of IGF2R (sIGF2R) is produced by proteolytic cleavage of the intact cellular receptor and is found at high levels in fetal and neonatal plasma. To test the hypothesis that sIGF2R modulates organ size in vivo, we generated transgenic mice expressing a mouse Igf2r complementary DNA in which the transmembrane domain sequence was deleted. The transgene was driven by the keratin-10 promoter and was expressed at the highest levels in the skin and alimentary canal. Transgenics showed disproportionately reduced size of the alimentary canal, where the wet weight was decreased by 9-20% and the dry weight was decreased by 20-30%, whereas the water content per unit dry weight was not significantly changed. In addition, the circulating levels of IGF-II and the latent form of transforming growth factor-beta1 were increased by 58-77% and 56-140%, respectively, whereas plasma epidermal growth factor levels showed a 24-35% reduction. The serum and tissue activities of four lysosomal enzymes were not affected, with the exception of the colon in the line expressing the transgene at highest levels, where enzyme activities were decreased compared with control values. These results support a significant role for the sIGF2R in local modulation of organ size in vivo.

Growth and the distal tip of mouse chromosome 7.

This review concerns the general problem of understanding growth control in the whole organism, starting with a saltatory change in size generated by a chromosome translocation or a mutation in a single gene. In particular, changes in insulin-like growth factor-II levels, by genetic and embryological manipulation, have major effects on wet weight size, but the intermediary events that link these levels to this measure of growth are uncertain. Thus it is currently impossible to eliminate any of the intermediary candidate processes that have been observed in model systems, including changed rates of apoptosis, cell multiplication, protein synthesis, capillary permeability and fluid transport.

Gi alpha 1 selectively couples somatostatin receptor subtype 3 to adenylyl cyclase: identification of the functional domains of this alpha subunit necessary for mediating the inhibition by somatostatin of cAMP formation.

A major cellular action of the neuropeptide somatostatin (SRIF) is the inhibition of adenylyl cyclase activity. SRIF induces this effect after its interaction with membrane-bound receptors. Five SRIF receptors (SSTRs), which differ in their functional coupling to adenylyl cyclase, have recently been cloned. The third SSTR cloned, SSTR3, effectively mediates the inhibition of adenylyl cyclase by SRIF. The molecular mechanism by which SRIF modulates intracellular cAMP synthesis via SSTR3 was investigated by initially identifying which G alpha subunits are involved in coupling SSTR3 to adenylyl cyclase. SRIF did not inhibit cAMP formation in Chinese hamster ovary cells stably expressing SSTR3 and Gi alpha 2 or Gi alpha 3 but lacking Gi alpha 1. However, SRIF did inhibit forskolin-stimulated cAMP formation in Chinese hamster ovary cells stably expressing SSTR3 and Gi alpha 1, indicating that Gi alpha 1 selectively couples SSTR3 to adenylyl cyclase. To investigate the functional domains of Gi alpha 1 necessary for interaction with SSTR3, a chimeric alpha subunit (Gi alpha 2/Gi alpha 1) was constructed, consisting of the amino-terminal two thirds of Gi alpha 2 ligated to the carboxyl-terminal third of Gi alpha 1. SRIF inhibited cAMP formation in cells expressing SSTR3 and the Gi alpha 2/Gi alpha 1 chimera. These findings indicate that the carboxy-terminal third of Gi alpha 1 interacts with SSTR3 and is important in transmitting the signal of SSTR3 activation to adenylyl cyclase. In contrast, a similar Gi alpha 2/Gi alpha 3 chimera did not couple SSTR3 to adenylyl cyclase, further indicating that Gi alpha 3 does not contribute to SRIF inhibition of adenylyl cyclase activity. These findings demonstrate that Gi alpha 1 selectively couples SSTR3 to adenylyl cyclase, and they indicate that the carboxyl-terminal region of this alpha subunit is involved in mediating SRIF inhibition of adenylyl cyclase activity.

Membrane-associated binding sites for indoleacetic acid in the rice coleoptile.

As described previously, the sensitivity of rice (Oryza sativa L.) coleoptiles to auxin is modulated by oxygen. Under anoxia, coleoptile elongation is insensitive to exogenously applied indole-3-acetic acid (IAA), whereas its sensitivity increases in air in the presence of the exogenous stimulus. Here we report the presence of two independent classes of membrane-bound IAA-binding sites in air-grown coleoptiles. Their binding activity is strictly correlated with the system's sensitivity to IAA. We designate them as site A (high affinity) and site B (low affinity). Site A shows a relatively fast response to anoxia, and is highly specific for auxins. Regulation of site-A binding activity through ATP, whose availability decreases under anoxia, is postulated. A role as auxin carrier is suggested for site B.