Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit. REPORT: Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. DISCUSSION: Homozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from 'Classical' OI. CONCLUSIONS: Here we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.

Case study of copper poisoning in a British dairy herd.

Following the initial diagnosis of chronic copper poisoning (CCP), the copper (Cu) status of a British dairy herd was investigated. Eight fatal cases of CCP were identified over a 17-month period, from December 1999 to May 2001, involving seven Jersey cows and one Holstein-Friesian; seven cows were dry when CCP occurred. Case diagnostic criteria were necrotising hepatopathy associated with abnormally high liver and kidney Cu concentrations. Analysis of the ration for the high-yielding Jersey cow group revealed about 50 mg Cu/kg dry matter intake (DMI). Risk factors predisposing to fatal CCP were Jersey breed, previous high yield, first two weeks of the dry period and moderately high dietary Cu (greater than 40 mg Cu/kg DMI).

Emergence of suspected type D botulism in ruminants in England and Wales (2001 to 2009), associated with exposure to broiler litter.

Scanning surveillance by the Veterinary Laboratories Agency revealed the emergence of suspected botulism in ruminants in 2003, presented as flaccid paralysis. From 2003 to 2009, 168 cattle and 19 sheep incidents were recorded, with mortality between 5 and 80 per cent. All sheep incidents and 95 per cent of cattle incidents had proximity to broiler litter. From July 2006, the gut contents collected from 74 affected cattle and 10 affected sheep were tested for Clostridium botulinum toxins using mice bioassays and for organisms by culture. Type D toxin was identified in 32 per cent of cattle and 18 per cent of sheep samples. C botulinum type D organisms were identified in 40 per cent of cattle and 30 per cent of sheep samples, but broth from one sample reacted with C and D antisera. Type C botulism has previously been reported more commonly than type D in the UK and has been associated with the use of poultry litter as fertiliser, bedding or feed. The almost exclusive association with C botulinum type D toxins or organisms in the gut contents in this survey suggests a change in the source or epidemiology of botulism in the UK. The source of C botulinum type D was uncertain. Broilers may carry C botulinum type D in their gut flora subclinically. The emergence of a new type D strain, or changes in broiler husbandry and nutrition, medication and other enteric infections may have affected colonisation with C botulinum. Further investigation of poultry and farm environments for sources of type D awaits the development of tests for C botulinum toxins that do not require the use of mice.

Oculoglandular syndrome caused by Yersinia pseudotuberculosis in a dairy goat.

An outbreak of ocular disease in a herd of housed dairy goats was characterized by severe granulomatous conjunctivitis and ipsilateral parotid and submandibular lymphadenopathy. In one case submitted for post-mortem examination, Yersinia pseudotuberculosis was isolated from both the conjunctiva and submandibular lymph node. Histopathological examination identified severe chronic active suppurative and lymphoplasmacytic conjunctivitis and suppurative and necrotizing lymphadenitis associated with bacteria of yersinial morphology. Similar pathological changes occur in Parinaud's oculoglandular syndrome in man due to infection with Y. pseudotuberculosis.

Haemoperitoneum associated with ovulation in women with bleeding disorders: the case for conservative management and the role of the contraceptive pill.

Haemoperitoneum secondary to ruptured corpus luteum is a rare complication for women on anticoagulants and with certain congenital bleeding disorders. A surgical approach is often taken, leading to oophorectomy in many cases. We describe three patients presenting with haemoperitoneum in association with factor VII deficiency, factor X deficiency and sitosterolaemia. In two of the patients, recurrent episodes occurred prior to introduction of the oral contraceptive pill. Conservative management with blood product and factor concentrate support was successful in avoiding surgery in three of the five episodes of bleeding. These cases demonstrate that preservation of ovarian function is possible with a conservative approach and recurrent episodes may be prevented by suppression of ovulation.

Prevalence of faecal excretion of verocytotoxigenic Escherichia coli O157 in cattle in England and Wales.

During the decade to 1999, the incidence of human infections with the zoonotic pathogen verocytotoxin-producing Escherichia coli O157 (VTEC O157) increased in England and Wales. This paper describes the results of a survey of 75 farms to determine the prevalence of faecal excretion of VTEC O157 by cattle, its primary reservoir host, in England and Wales. Faecal samples were collected from 4663 cattle between June and December 1999. The prevalence of excretion by individual cattle was 4.2 per cent (95 per cent confidence interval [CI] 2.0 to 6.4) and 10.3 per cent (95 per cent CI 5.8 to 14.8) among animals in infected herds. The within-herd prevalence on positive farms ranged from 1.1 to 51.4 per cent. At least one positive animal was identified on 29 (38.7 per cent; 95 per cent CI 28.1 to 50.4) of the farms, including dairy, suckler and fattening herds. The prevalence of excretion was least in the calves under two months of age, peaked in the calves aged between two and six months and declined thereafter. The phage types identified most widely were 4, 34 and 2, which were each found on six of the 29 positive farms.

Kikuchi-Fujimoto disease: a rare but important cause of lymphadenopathy.

UNLABELLED: Cervical lymphadenopathy is a common problem in children. Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis) is a rare condition that causes persistent lymphadenopathy and has a characteristic histological appearance. Kikuchi-Fujimoto disease is well recognized in Japan, where it was first described, but descriptions in the paediatric literature are sparse. Paediatricians may therefore be unaware of this rare but important condition. The case is described of a 14-y-old girl suffering from fatigue, weight loss, night sweats and lymphadenopathy. The predominance of systemic symptoms prompted an extensive investigation. The diagnosis of Kikuchi-Fujimoto disease was made after direct histological examination of a lymph node biopsy. The case illustrates the clinical features of this little-known condition and highlights the potential confusion with other diagnoses. The pathological features are discussed and the literature reviewed. CONCLUSION: Kikuchi-Fujimoto disease should be considered in cases of persistent lymphadenopathy. An early biopsy can be instrumental in preventing unnecessary investigations and potentially harmful treatments.

Hormonal regulation of oxytocin-induced prostaglandin F(2alpha) secretion by the bovine and ovine uterus in vivo.

In long-term ovariectomized ewes and cows, endometrial oxytocin receptors rest at relatively high levels but oxytocin is unable to induce prostaglandin F(2alpha) release. A series of studies were carried out to investigate the roles of physiological levels of progesterone and estradiol in "activating" these receptors in terms of permitting oxytocin-induced prostaglandin F(2alpha) release. In long-term ovariectomized cows, treatment with progesterone, but not estradiol, resulted in the induction of responsiveness to oxytocin. This responsiveness appeared within 2 d of progesterone treatment, reached a maximum by 6 d and was maintained to Day 18. In ovariectomized ewes, while estradiol treatment did induce temporary responsiveness to oxytocin after 3 d of treatment, treatment with progesterone was required to induce sustained responsiveness that appeared by Day 9 of treatment and was maintained to Day 12. Measurement of endometrial receptors for oxytocin revealed a significant decline in oxytocin receptors by Day 6 of progesterone treatment when responsiveness to oxytocin was maximal, demonstrating that receptor concentrations were not a limiting factor. The most likely mechanism by which progesterone treatment induces responsiveness to oxytocin may be through the up regulation of post receptor signaling pathways and/or enzymes involved in prostaglandin synthesis.

The marginal seal of Class II restorations: flowable composite resin compared to injectable glass ionomer.

The objective of this study was to investigate the effect of a flowable composite resin (Tetric Flow) versus an injectable glass ionomer (Fuji II LC) on microleakage at the cavosurface margin of the proximal box of Class II restorations in permanent teeth in-vitro. Thirty caries and restoration-free human bicuspids were prepared with mesial and distal slot preparations and were filled either with a bonding agent (Optibond) plus a flowable composite resin (Tetric Flow), Group I; bonding agent (Optibond) plus a flowable glass ionomer (Fuji II LC), Group II; or a flowable glass ionomer (Fuji II LC) with no bonding agent, Group III. All specimens were then immersed in a 2% solution of basic fuschin dye for 24 hours to allow for dye penetration into possible existing gaps. These teeth were then carefully sectioned mesially/distally into two pieces using an Isomet saw. The teeth were then studied under a binocular microscope to measure depths of dye penetrations as an indication of marginal microleakage at the gingival cavosurface margin and scored as follows: 0 = no dye penetration, 1 = dye penetration into enamel only, 2 = dye penetration into enamel and dentin, 3 = dye penetration into the pulp. The specimens were also evaluated using a SEM. The results showed that there were statistically significant differences between Groups I (Tetric Flow) and (Fuji II LC plus bonding agent), II in favor of Group I; between Groups I and (Fuji II LC with no bonding agent), III in favor of Group I; as well as Groups II and III in favor of Group II (Fuji II LC plus bonding agent). Group I (bonding agent plus flowable composite resin) showed significantly less microleakage. Group II (bonding agent plus flowable glass ionomer) demonstrated a bond that existed between the bonding agent and the glass ionomer but microleakage within microgaps of the glass ionomer itself Group III (flowable glass ionomer plus no bonding agent) demonstrated significant microleakage between the glass ionomer and tooth structure, microgaps within the glass ionomer, and lack of retention of the restoration. It appears that the use of a flowable composite resin (Tetric Flow) plus a bonding agent (Optibond) in the proximal box of a Class II restoration in permanent teeth will significantly reduce the microleakage at the cavosurface margin when compared with an injectable glass ionomer (Fuji II LC) with or without a bonding agent (Optibond).

Laparoscopic staging of malignant disease.

The earliest applications of laparoscopy were for diagnostic procedures. The goal was to make a diagnosis while sparing the patient a major, and often futile, operation. However, the view was limited and it was not possible to palpate organs or masses. The recent development of advanced laparoscopic techniques and ultrasound have improved our view and restored our "sense of touch". These innovations bring the goal of minimally invasive diagnosis and staging closer to reality. This paper reviews the current literature on the laparoscopic staging of cancer with an emphasis on patient selection, diagnostic accuracy, and the reduction in morbidity which can be achieved.

Advanced laparoscopy: "the next generation". The adrenal, kidney, spleen, pancreas, and liver.

Following the rapid acceptance of laparoscopic cholecystectomy, a few adventurous surgeons "dared to boldly go where no one had gone before." They sought to achieve the same reduction in morbidity while accomplishing the same surgical goals. This paper will briefly review the current status of minimal access surgery for the solid organs of the abdomen. It will focus on the indications, risks, limitations, and on the balance between the trauma of access and the trauma of the procedure itself. As new techniques and equipment emerge and experience and data are accumulated, this balance may shift. Some of these procedures are in their infancy while others are rapidly becoming the new "Gold Standard".

Role of early luteal phase progesterone in control of the timing of the luteolytic signal in cows.

The effects of the pattern and concentration of early luteal phase progesterone on subsequent prostaglandin F2 alpha release in response to exogenous oxytocin was investigated during simulated luteal phases in ovariectomized cows treated with progesterone and oestradiol in patterns designed to simulate the range of luteal phase concentrations that occur naturally. In the first experiment, three groups of four cows received different concentrations of early luteal phase progesterone to determine the effective concentration in terms of cycle control. The results show that a plasma progesterone concentration early in the luteal phase as low as 0.6 ng ml-1 was sufficient to affect the timing of the subsequent luteolytic signal. In the second experiment, an early (day 1), a normal (day 4) or a late (day 7) postovulatory increase in progesterone was recreated in three groups of four cows. Responsiveness to oxytocin in the early progesterone group developed 3 days earlier than in the normal progesterone group, demonstrating the ability of early progesterone to advance the luteolytic signal. However, in the late progesterone group, there was no delay in the development of responsiveness to oxytocin compared with the normal progesterone group, demonstrating that the luteolytic signal is programmed to occur by a given time, irrespective of the early progesterone pattern. This demonstrates that a factor other than the timing of the early luteal phase progesterone increase ultimately must control the timing of luteolysis in cows.

Effect of adrenalin and propranolol on progesterone and oxytocin secretion in vivo during the caprine estrous cycle.

The effects of jugular infusions of adrenalin and the beta-adrenergic receptor antagonist propranolol on plasma concentrations of progesterone and oxytocin were examined at 2 different stages of the caprine estrous cycle. Adrenalin (25 micrograms.kg-1h-1) significantly (P < 0.05) increased oxytocin secretion on Day 3 and Day 10 of the cycle (estrus = Day 0); progesterone concentrations were significantly (P < 0.05) elevated on Day 10 alone. Propranolol had no effect on progesterone secretion yet significantly (P < 0.05) reduced oxytocin concentrations on Day 3. These results suggest that there may be neuroendocrine involvement in the regulation of luteal oxytocin secretion in the goat.

Effects of arterial infusions of adrenalin and acetylcholine on luteal secretion of progesterone and oxytocin in goats.

The effects of close intra-arterial infusion of acetylcholine and adrenalin on ovarian secretion of progesterone and oxytocin were examined on Day 10 of the estrous cycle in goats (estrus = Day 0). Acetylcholine (15 micrograms/min) was without effect, but adrenalin (10 micrograms/min) significantly (P < 0.001) raised both progesterone and oxytocin concentrations in ovarian vein plasma. These results show that luteal hormone secretion is enhanced in the goat by beta-adrenergic stimulation and suggest that, as in the sheep and cow, there may be neuroendocrine involvement in the regulation of caprine luteal function.

Telementoring. A practical option in surgical training.

BACKGROUND: Telemedicine offers significant advantages in bringing consulting support to distant colleagues. There is a shortage of surgeons trained in performing advanced laparoscopic operations. AIM: Our aim was to evaluate the role of telementoring in the training of advanced laparoscopic surgical procedures. METHODS: Student surgeons received a uniform training format to enhance their laparoscopic skills and intracorporeal suturing techniques and specific procedural training in laparoscopic colonic resections and Nissen fundoplication. Subsequently, operating rooms were equipped with three cameras. Telestrator (teleguidance device), instant replay (to critique errors), and CD-ROM programs (to provide information of reference) were used as intraoperative educational assistance tools. In phase I, four colonic resections were performed with the mentor in the operating room (group A) and four colonic resections were performed with the mentor on the hospital grounds, but not in the operating room (group B). The voice and video signals were received at the mentor's location, using coaxial cable. In phase II, two Nissen fundoplications were performed with the mentors in the operating room (group C) and two Nissen fundoplications were performed with the mentors positioned five miles away from the operating room (group D), using currently existing land lines at the T-1 level. RESULTS: There were no differences in the performances of the surgeons and outcome of the operations between groups A & B and C & D. It was possible to tackle the intraoperative problems effectively. CONCLUSIONS: The telementoring concept is potentially a safe and cost-effective option for advanced training in laparoscopic operations. Further investigation is necessary before routine transcontinental patient applications are attempted.