Biomedical subjects
Publications and source records attributed to A J Millar.
Links are being discovered between the circadian clock mechanisms in different species. The Neurospora Frequency protein has a rhythm of abundance and phosphorylation similar to that of the Drosophila Period protein, and Neurospora and mouse clock components, like Period, have 'PAS' domains.
A wide range of biological processes, in all eukaryotes and in some prokaryotes, are controlled by rhythms with a period close to 24 hours. The circadian oscillator, which is responsible for generating these rhythms, is controlled by light signals that maintain its synchrony with the environmental day/night cycle. Higher plants exhibit many circadian rhythms, including rhythms in the transcription of specific genes. Molecular tools derived from such clock-controlled genes have led to the identification of several circadian rhythm mutants in the genetic model, Arabidopsis thaliana. The extensive understanding of photoperception in this species will make it a powerful system with which to investigate the light regulation of circadian rhythms. We compare Arabidopsis rhythms to the results from other systems, and discuss these data with respect to the current phototransduction models.
This paper records our experience in the management of 25 sets of conjoined twins seen over a 32 year period (1964 - 1996). The twins were classified into 14 complete and symmetrical sets and 11 incomplete or heteropagus. The 14 symmetrical sets included 9 thoracopagus, 2 ischiopagus, 1 craniopagus and 1 omphalopagus twins. In the incomplete heteropagus group there was 1 ischiopagus, one twin being anencepahlic, 2 dipygus, 5 parasitic, 2 fetus-in-fetu and I cranial and caudal. The management is detailed case by case. Overall 10 of 14 symmetrical sets underwent attempts at separation with 16 surviving the procedure, but there were 3 late deaths. In the incomplete group 10 of 11 were operated on with 9 survivors. The importance of a multi-disciplinary approach, the extensive investigations required pre-operatively to define areas of organ and bony conjunction, congenital anomalies of each twin and surgical teamwork is emphasized. Specific problems encountered were identified. In thoracopagus twins the hearts were of paramount importance as conjuction was usually fatal, being associated with major congenital defects. The greater the extent of thoracic cage fusion the greater the chance of associated severe anomaly. Skin expansion to assist coverage of the defects after separation was of great assistance, as was the use of collagen coated vicryl. Evaluation of the liver and pancreatico-biliary systems with isotope excretion scanning was crucial to pre-operative planning. Where there was fusion of the duodenum a single pancreatico-biliary system could be expected and prior strategies for separation and Roux-en-Y enteric drainage of both pancreatic and biliary secretion should be planned. Gastro-oesophageal reflux led to considerable morbidity in both twins of a thoraco-omphalopagus set. In ischiopagus and dipygus conjoined twins bilateral posterior iliac osteotomies were an essential component to anatomic reconstruction of the pelvic ring and wound closure. Also in this group, due to the frequency and extent of shared genital, urinary and ano-rectal structures, long-term morbidity was expected and a component of this might be due to spinal cord tethering, or as in one of our cases, a progressive hydrosyringomyelia. Timing of separation was ideally set at between 5 and 9 months with 6 to 8 weeks of prior tissue expansion but earlier operation was frequently required because of cardio-respiratory problems or organ failure in one twin. In most cases the goal of obtaining separate, independent and intact individuals was achieved.
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A high incidence (28 per 100,000 admissions) of liver abscesses is reported in children from the Western Cape Province of South Africa. Of a total of 84 childhood hepatic abscesses over a 10-year period, 51 per cent (43 patients) were primary pyogenic, 30 per cent (25 patients) amoebic, 2 per cent (two patients) Ascaris, and 17 per cent (14 patients) were culture negative. Protein calorie malnutrition was evident in 56 per cent of cases. Amoebic abscesses originated in patients from rural areas, whereas pyogenic abscesses occurred in patients from urban and periurban environments. Staphylococcus aureus was cultured in 85 per cent of pyogenic liver abscesses. Gram negative organisms were identified in four cases of amoebic hepatic abscess where secondary infection occurred. Co-existing parasites of Ascaris lumbricoides and Trichuris trichiura were identified in the stools of 31 per cent of patients. A low (4.8 per cent) mortality is reported for this series.
BACKGROUND: Gastroesophageal reflux is part of a generalized foregut motility disorder, which may also include delayed gastric emptying. With persistence of gastroesophageal reflux, or the presence of complications, including recurrent aspiration syndrome and esophageal stricture formation, surgical correction may be indicated. It is uncertain whether a procedure to resolve delayed gastric emptying is indicated at this time as well. METHODS: Sixty-seven children with proven gastroesophageal reflux had preoperative gastric emptying assessed using 99Technetium-Sn-colloid labelled milk. Delayed gastric emptying was defined as a gastric residual activity of more than 40% at 2 hours after feeding. The antireflux operation was a partial anterior fundoplication. Postoperative milk scans assessed the effect of surgery on gastric emptying. RESULTS: Gastric emptying at 2 hours improved overall from a median of 22% before surgery to 17% after surgery. In 17 patients delayed gastric emptying was identified before surgery; in 15 of those it returned to within normal limits after surgery. In 50 children with normal gastric emptying before surgery (gastric residual activity at 2 hours 16%), 14 (28%) showed delayed gastric emptying in the postoperative scan. CONCLUSIONS: Delayed gastric emptying is common in children who undergo surgery for gastroesophageal reflux disease. A partial anterior fundoplication antireflux operation improves gastric emptying to within normal limits in the majority (88%) in this group, rendering a synchronous gastric drainage procedure unnecessary.
In higher plants, environmental cues such as light signals are integrated with circadian clock signals to control precisely the daily rhythms observed for many biological functions. We have used a fusion of the promoter of a chlorophyll a/b binding protein gene, CAB2, with firefly luciferase (cab2::luc) to monitor the detailed kinetics of transcription in response to photoreceptor activation in Arabidopsis. Using this marker in phototransduction and circadian-dysfunctional mutants, we studied how signals from phytochrome and the circadian clock are integrated for the regulation of CAB2 transcription. Results from these mutant studies demonstrate that similar expression features, namely, the acute and circadian responses, are present in both etiolated and green seedlings and that the acute and circadian responses are genetically separable. We also demonstrate that persistent Pfr signaling occurs in red light-pulsed etiolated seedlings, which suggests that the circadian clock antagonizes Pfr-mediated signal transduction. Based on these genetic studies, we propose a model for the regulation of CAB2 transcription in which individual photoreceptors and phototransduction components have been assigned to specific pathways for the regulation of discrete kinetic components of the CAB2 expression pattern.
Impalpable testes constitute up to 20% of cases of undescended testes and present both a diagnostic and a therapeutic problem. Knowledge of testicular site prior to orchidopexy is useful in planning surgical strategy. Misdirected blind inguinal exploration can be avoided. Many imaging techniques are time-consuming and expensive and can neither confidently locate an impalpable testis nor exclude its absence. Recently laparoscopy has been advocated as a safe and efficient method of identifying presence and site of an impalpable testis. The first stage of a divided-vessel orchidopexy may also be performed simultaneously. Fifty children with 60 impalpable testes--40 unilateral and 10 bilateral--underwent laparoscopic examination prior to groin exploration. In 5 (8%) an inguinal testis was found which had been missed on pre-operative palpation. The testis was absent in 23 (38%), of whom 13 had a limited negative groin exploration because cord structures were seen entering the internal ring. In 30 (50%) an intra-abdominal testis was identified; 14 were relocated into the scrotum with a standard orchidopexy, 16 required a divided-vessel orchidopexy. In 2 (4%) intra-abdominal testicular remnants were removed. There was no operative morbidity. We conclude that laparoscopy is a useful technique in the management of children with impalpable testes. Open perumbilical insertion of the trochar is a safe method of introducing the telescope into the peritoneal cavity. In addition to accurately identifying a testis in 60%, 40% were spared the pain and morbidity of an extensive groin exploration.
OBJECTIVE: Review of the biliary complications following orthotopic liver transplantation (OLT) at our institution, and their management and outcome. DESIGN: Retrospective study of medical records of 63 patients who underwent 68 transplant operations. SETTING: The Liver Transplant Unit, Groote Schuur Hospital and Red Cross War Memorial Children's Hospital, Cape Town PATIENTS: Six patients treated for 9 biliary complications. INTERVENTIONS: Reoperation with biliary reconstruction, or non-operative measures by either endoscopic retrograde pancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC). OUTCOME MEASURES: Clinical outcome and survival following treatment for biliary complications. RESULTS: Biliary complications occurred in 8.8% of patients who underwent transplantation at our institution. These consisted of strictures in 4 patients (with leak in 2), bile leak in 1 patient, and unsuspected primary sclerosing cholangitis (PSC) of the recipient duct in 1 patient. The mean time interval of biliary complications following OLT was 8 weeks (range 3-16). Biliary reconstruction was required in 4 patients while 2 patients were treated by endoscopic stenting. After a mean follow-up period of 30 months (range 1-64), 4 patients remained stable, 1 patient developed progressive stricturing of the intrahepatic ducts requiring repeated PTC dilatations, and 1 patient experienced stent blockages requiring endoscopic stent changes (died of unrelated causes). CONCLUSIONS: The rate of biliary complications following OLT at our institution compares favourably with literature reports. While biliary reconstruction is usually needed, endoscopic stenting appears effective in selected cases of biliary stricture and leak. PSC should be excluded prior to transplantation in young patients with cryptogenic cirrhosis.
Controversy persists with regard to the diagnosis and treatment of the acute scrotum in children. The differential diagnosis includes torsion of the testis, torsion of one of the appendices testis and epididymo-orchitis. Clinical differentiation is notoriously difficult and our policy has been to explore the scrotum of all who present with signs of an acute scrotum. The medical records of 199 boys aged less than 13 years who presented with an acute scrotum at Red Cross War Memorial Children's Hospital in Cape Town during the period 1970-1996 were retrospectively reviewed. Diagnosis was made clinically in all cases. Sixty-two boys (31%) were found on exploration to have torsion of the testis (mean age 6.3 years), the left side being affecting 2.5 times more frequently than the right (1 neonate had bilateral torsion), 62 (31%) had torsion of testicular appendages and 56 (28%) had epididymo-orchitis. Nineteen were grouped separately and 13 (6.5%) of these were treated conservatively. Boys needing an orchidectomy (N = 38) for testicular torsion presented three times later than those who did not (48 v. 16.5 hours). Successful conservation of the testis was directly related to the time interval of symptom development and surgical derotation. Boys with torsion of a testicular appendage presented later (mean 51 hours) and were older (mean 10 years) than boys in the other two groups. Those with epididymo-orchitis were younger (mean 3.3 years) and 40% were younger than 1 year. Only in one-third was there any clinical supportive evidence of the diagnosis. Surgical complications were infrequent. We advocate expedient surgical exploration and derotation with contralateral orchidopexy, since clinical differentiation between torsion of the testis, testicular appendages and epididymo-orchitis is inexact, even with highly specialised investigation such as Doppler ultrasound and radionuclide scanning, which may not be widely available, may delay definitive treatment and suggest a lack of urgency where time is of the essence.
The transcription of CAB genes, encoding the chlorophyll a/b-binding proteins, is rapidly induced in dark-grown Arabidopsis seedlings following a light pulse. The transient induction is followed by several cycles of a circadian rhythm. Seedlings transferred to continuous light are known to exhibit a robust circadian rhythm of CAB expression. The precise waveform of CAB expression in light-dark cycles, however, reflects a regulatory network that integrates information from photoreceptors, from the circadian clock and possibly from a developmental program. We have used the luciferase reporter system to investigate CAB expression with high time resolution. We demonstrate that CAB expression in light-grown plants exhibits a transient induction following light onset, similar to the response in dark-grown seedlings. The circadian rhythm modulates the magnitude and the kinetics of the response to light, such that the CAB promoter is not light responsive during the subjective night. A signaling pathway from the circadian oscillator must therefore antagonize the phototransduction pathways controlling the CAB promoter. We have further demonstrated that the phase of maximal CAB expression is delayed in light-dark cycles with long photoperiods, due to the entrainment of the circadian oscillator. Under short photoperiods, this pattern of entrainment ensures that dawn coincides with a phase of high light responsiveness, whereas under long photoperiods, the light response at dawn is reduced.
Photoperiodic responses, such as the daylength-dependent control of reproductive development, are associated with a circadian biological clock. The photoperiod-insensitive early-flowering 3 (elf3) mutant of Arabidopsis thaliana lacks rhythmicity in two distinct circadian-regulated processes. This defect was apparent only when plants were assayed under constant light conditions. elf3 mutants retain rhythmicity in constant dark and anticipate light/dark transitions under most light/dark regimes. The conditional arrhythmic phenotype suggests that the circadian pacemaker is intact in darkness in elf3 mutant plants, but the transduction of light signals to the circadian clock is impaired.
Abdominal aortic aneurysms are rare in children. Causes include mycotic aneurysms, vasculitides (eg, Takayasu's arteritis), connective tissue diseases (eg, Marfan's syndrome, Ehlers-Danlos syndrome, and tuberous sclerosis) and traumatic false aneurysms. Four cases are described. Case 1 was a 12-year-old boy who presented with an acute unheralded rupture of the subdiaphragmatic aorta accompanied by lower limb paralysis and ischemia. Attempted repair failed because of extensive friability of the large arteries. Histological evaluation confirmed cystic medial necrosis despite Marfanoid phenotype. Cases 2 and 3 were boys aged 12 and 11 with Takayasu's arteritis who presented with hypertensive encephalopathy and heart failure. Although both had involvement of the origins of the renal arteries, one aneurysm was predominantly suprarenal and the other infrarenal. Currently both children are being managed successfully with antihypertensive therapy. Case 4 was a 5-year-old girl who presented with hypertension and a pulsatile abdominal mass after treatment of infective endocarditis 18 months previously. Arteriography and three-dimensional computed tomography confirmed an aneurysm (6 x 5 x 4 cm) arising from the aorta and involving the right renal artery. Aneurysmectomy, removal of a small ischemic right kidney, and Gore-Tex grafting resulted in cure of the hypertension and uneventful recovery. The present series confirms that rupture is a fatal complication, renovascular complications are common, and medical control of hypertension is an essential part of management. Management strategies need to be highly individualized, and may be successful without surgical intervention. Close clinical and ultrasound follow-up of those managed nonoperatively is essential.
Iatrogenic esophageal perforations in children are rare. To evaluate patterns of injury, clinical presentation, and treatment options for such patients, the authors reviewed the case records of 11 children who had sustained transmural injury to the esophagus during a dilatation procedure at their institution between 1967 and 1994. Strictures requiring dilatation were attributable to caustic ingestion in eight, esophageal atresia repair in two, and congenital stenosis in one. Eight were penetrating injuries, and three were disruptions. Two involved the cervical esophagus; and nine involved the thoracic esophagus. Pain, pyrexia, and tachycardia were early signs. Proximal thoracic perforations led to signs in the left chest region (effusion/pneumothorax); with distal perforation the signs were on the right side. Treatment along conventional lines (local drainage, gastrostomy, primary repair after early recognition, and antibiotic therapy) was successful, with two major complications, both empyemas. The most recent case, a disruption of a tracheoesophageal fistula stricture, was successfully treated with oral water irrigation and antibiotics only. Six had colonic interposition (all caustic ingestion), one required endoesophageal resection of a distal stricture, and four had resolution of the stricture, three without additional dilatation. The majority of children with iatrogenic injuries of the esophagus can be managed successfully by conservative measures and pleural drainage, with surgical procedures reserved for large disruptions of the esophagus, intraabdominal perforations, and cases that do not respond to appropriate conservative measures. Patients with caustic injury to the esophagus have a greater risk for the development of penetrating injury, and this may be one indicator of the severity of scarring. There are distinct clinical patterns of presentation, which depend on the level at which the esophagus is perforated. Dilatation disruption of a localized stricture has a good long-term prognosis for the esophagus and may even cure the stricture. The role of oral irrigation still must be fully evaluated where disruption has occurred as distinct from a penetrating injury.
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The cycling bioluminescence of Arabidopsis plants carrying a firefly luciferase fusion construct was used to identify mutant individuals with aberrant cycling patterns. Both long- and short-period mutants were recovered. A semidominant short-period mutation, timing of CAB expression (toc1), was mapped to chromosome 5. The toc1 mutation shortens the period of two distinct circadian rhythms, the expression of chlorophyll a/b-binding protein (CAB) genes and the movements of primary leaves, although toc1 mutants do not show extensive pleiotropy for other phenotypes.
Transgenic Arabidopsis plants expressing a luciferase gene fused to a circadian-regulated promoter exhibited robust rhythms in bioluminescence. The cyclic luminescence has a 24.7-hour period in white light but 30- to 36-hour periods under constant darkness. Either red or blue light shortened the period of the wild type to 25 hours. A phytochrome-deficient mutation lengthened the period in continuous red light but had little effect in continuous blue light, whereas seedlings carrying mutations that activate light-dependent pathways in darkness maintained shorter periods in constant darkness. These results suggest that both phytochrome- and blue light-responsive photoreceptor pathways control the period of the circadian clock.