Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia

Flanagan SE, Kapoor RR, Banerjee I, Hall C, Smith VV, Hussain K, Ellard S. Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia. Recessive inactivating mutations in the ABCC8 and KCNJ11 genes encoding the adenosine triphosphate‐sensitive potassium (K_ATP) channel subunit sulphonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel subunit (Kir6.2) are the most common cause of hyperinsulinaemic hypoglycaemia (HH). Most of these patients do not respond to treatment with the K_ATP channel agonist diazoxide. Dominant inactivating ABCC8 and KCNJ11 mutations are less frequent, but are usually associated with a milder form of hypoglycaemia that is responsive to diazoxide therapy. We studied five patients from four families with HH who were unresponsive to diazoxide and required a near total pancreatectomy. Mutations in KCNJ11 and ABCC8 were sought by sequencing and dosage analysis. Three novel heterozygous ABCC8 mis‐sense mutations (G1485E, D1506E and M1514K) were identified in four probands. All the mutations affect residues located within the Nucleotide Binding Domain 2 of the SUR1 subunit. Testing of family members showed that the mutations had arisen de novo with dominant inheritance in one pedigree. This study extends the clinical phenotype associated with dominant K_ATP channel mutations to include severe congenital HH requiring near total pancreatectomy in addition to a milder form of diazoxide responsive hypoglycaemia. The identification of dominant vs recessive mutations does not predict clinical course but it is important for estimating the risk of HH in future siblings and offspring.     

The antimicrobial resistance patterns and associated determinants in Streptococcus suis isolated from humans in southern Vietnam, 1997-2008

Background

Our objective was to determine the frequency and determinants of presentation to care with advanced HIV disease in patients who discover their HIV diagnosis at this stage as well as those with delayed presentation to care after HIV diagnosis in earlier stages.

Methods

We collected data on 1,819 HIV-infected patients in Brussels (Belgium) and Northern France from January 1997 to December 2007. "Advanced HIV disease" was defined as CD4 count <200/mm³ or clinically-defined AIDS at study inclusion and was stratified into two groups: (a) late testing, defined as presentation to care with advanced HIV disease and HIV diagnosis ≤6 months before initiation of HIV care; and (b) delayed presentation to care, defined as presentation to care with advanced HIV disease and HIV diagnosis >6 months before initiation of HIV care. We used multinomial logistic regression to determine the factors associated with delayed presentation to care and late testing.

Results

Of the 570 patients initiating care with advanced HIV disease, 475 (83.3%) were tested late and 95 (16.7%) had delayed presentation to care. Risk factors for delayed presentation to care were: age 30-50 years, injection drug use, and follow-up in Brussels. Risk factors for late testing were: sub-Saharan African origin, male gender, and older age. HIV transmission through heterosexual contact was associated with an increased risk of both delayed presentation to care and late testing. Patients who initiated HIV care in 2003-2007 were less likely to have been tested late or to have a delayed presentation to care than patients who initiated care before 2003.

Conclusion

A considerable proportion of HIV-infected patients present to care with advanced HIV disease. Late testing, rather than a delay in initiating care after earlier HIV testing, is the main determinant of presentation to care with advanced HIV disease. The factors associated with delay presentation to care differ from those associated with late testing. Different strategies should be developed to optimize early access to care in these two groups.     

Familial Kaposi's sarcoma and Paget's disease of bone

Familial Kaposi's sarcoma and familial Paget's disease of bone have not previously been reported to occur in the one patient or the one family. We report on an 82-year-old female of Lebanese descent who was recently diagnosed with Kaposi's sarcoma and Paget's disease. Of the patient's eight siblings, seven had Paget's disease and two of these also had Kaposi's sarcoma. Histocompatibility leucocyte antigen (HLA) class I and II typing of the patient showed: A2, A3; B35, Bx; Bw6; Cw4; DRβ1*1101 (an HLA-DR5 subtype) DRβ3 and DQβ1*0301. Previous reports have described possible associations of familial Kaposi's sarcoma with HLA-DR5 and Paget's disease with DR2, DRβ1*1104, DPβ1*04and DQw1. Genetic factors and possible viral aetiologies fur each condition are reviewed.     

Vascularized fibular graft in infected tibial bone loss

Background:

The treatment options of bone loss with infections include bone transport with external fixators, vascularized bone grafts, non-vascularized autogenous grafts and vascularized allografts. The research hypothesis was that the graft length and intact ipsilateral fibula influenced hypertrophy and stress fracture. We retrospectively studied the graft hypertrophy in 15 patients, in whom vascularized fibular graft was done for post-traumatic tibial defects with infection.

Materials and Methods:

15 male patients with mean age 33.7 years (range 18 - 56 years) of post traumatic tibial bone loss were analysed. The mean bony defect was 14.5 cm (range 6.5 – 20 cm). The mean length of the graft was 16.7 cm (range 11.5 – 21 cm). The osteoseptocutaneous flap (bone flap with attached overlying skin flap) from the contralateral side was used in all patients except one. The graft was fixed to the recipient bone at both ends by one or two AO cortical screws, supplemented by a monolateral external fixator. A standard postoperative protocol was followed in all patients. The hypertrophy percentage of the vascularized fibular graft was calculated by a modification of the formula described by El-Gammal. The followup period averaged 46.5 months (range 24 – 164 months). The Pearson correlation coefficient (r) was worked out, to find the relationship between graft length and hypertrophy. The t-test was performed to find out if there was any significant difference in the graft length of those who had a stress fracture and those who did not and to find out whether there was any significant difference in hypertrophy with and without ipsilateral fibula union. The Chi square test was performed to identify whether there was any association between the stress fracture and the fibula union. Given the small sample size we have not used any statistical analysis to determine the relation between the percentage of the graft hypertrophy and stress fracture.

Results:

Graft union occurred in all patients in a mean time of 3.3 months, at both ends. At a minimum followup of 24 months the mean hypertrophy noted was 63.6% (30 – 136%) in the vascularized fibular graft. Ten stress fractures occurred in seven patients. The mean duration of the occurrence of a stress fracture in the graft was 11.1 months (2.5 – 18 months) postoperatively. The highest incidence of stress fractures was when the graft hypertrophy was less than 20%. The incidence of stress fractures reduced significantly after the graft hypertrophy exceeded 20%.

Conclusion:

In most cases hypertrophy of the vascularized fibular graft occurs in response to mechanical loading by protected weight bearing, and the amount of hypertrophy is variable. The presence or absence of an intact fibula has no bearing on the hypertrophy or incidence of stress fracture. The length of the fibular graft has no bearing on the hypertrophy or stress fracture.     

Hepatolithiasis with biliary ascariasis – a case report

Background  

Biliary ascariasis is regarded as possible etiological factor for hepatolithiasis. Here we report one case of a patient with hepatolithiasis with biliary ascariasis who developed a liver abscess, which was treated with partial hepatectomy.     

Proliferative and inflammatory factors in the vitreous of patients with proliferative diabetic retinopathy

Purpose:

The purpose was to measure the concentrations of various cytokines and growth factors (including vascular endothelial growth factor [VEGF] and pigment epithelium-derived factor [PEDF]) in the vitreous of patients with proliferative diabetic retinopathy (PDR) and to investigate interaction between inflammatory and proliferative factors in the genesis of PDR.

Materials and Methods:

Vitreous samples from 32 eyes with PDR and 25 eyes without diabetes mellitus and signs of DR (control) were collected. Vitreous concentrations of VEGF, PEDF, monocyte chemotactic protein-1 (MCP-1), interleukin-4 (IL-4), IL-6, IL-8, IL-10, IL-17A, and secretory immunoglobulin A (sIgA) were simultaneously measured using enzyme-linked immunoassay.

Results:

Vitreous levels of VEGF, PEDF, IL-17A, IL-6, IL-8, IL-4, and sIgA were significantly (Π < 0.05) higher in eyes with PDR compared to control. The concentration of VEGF was more than 17-times higher than in control, and the concentration of PEDF was not changed oppositely and was also higher (1.45-times) compared to control, that may indicate disturbances of compensatory mechanisms in angiogenesis regulation in PDR. Significant (P < 0.05) positive correlations were observed between vitreous concentrations of VEGF and IL-17A (r = 0.45), VEGF and IL-8 (r = 0.48), VEGF and IL-4 (r = 0.51), PEDF and IL-17A (r = 0.48), PEDF and IL-8 (r = 0.59), MCP-1 and PEDF (r = 0.72), MCP-1 and IL-8 (r = 0.45), IL-4 and IL-17A (r = 0.65), IL-4 and IL-8 (r = 0.71), IL-8 and IL-17A (r = 0.59).

Conclusions:

Significantly raised levels of inflammatory and proliferative factors and numerous positive correlations between them may demonstrate a significant role of activation of vascular proliferation and local inflammation in the pathogenesis of PDR.     

Genetics of acute and chronic pancreatitis: An update

Progress made in identifying the genetic susceptibility underlying acute and chronic pancreatitis has benefitted the clinicians in understanding the pathogenesis of the disease in a better way. The identification of mutations in cationic trypsinogen gene(PRSS1 gene; functional gain mutations) and serine protease inhibitor kazal type 1(SPINK1 gene; functional loss mutations) and other potential susceptibility factors in genes that play an important role in the pancreatic secretory functions or response to inflammation during pancreatic injury has changed the current concepts and understanding of a complex multifactorial disease like pancreatitis. An indi-vidual's susceptibility to the disease is governed by ge-netic factors in combination with environmental factors. Candidate gene and genetic linkage studies have iden-tified polymorphisms in cationic trypsinogen(PRSS1), SPINK1, cystic fibrosis trans-membrane conductance regulator(CFTR), Chymotrypsinogen C(CTRC), Ca-thepsin B(CTSB) and calcium sensing receptor(CASR). Individuals with polymorphisms in the mentioned genes and other as yet identified genes are at an enhanced risk for the disease. Recently, polymorphisms in genes other than those involved in "intra-pancreatic trypsin regulatory mechanism" namely Claudin-2(CLDN2) andCarboxypeptidase A1(CPA1) gene have also been iden-tified for their association with pancreatitis. With ever growing number of studies trying to identify the genetic susceptibility in the form of single nucleotide polymor-phisms, this review is an attempt to compile the avail-able information on the topic.     

Sleep disturbances and a risk of myocardial infarction

The aim of the study was to investigate the influence of sleep disturbances on the 8-year risk of myocardial infarction (MI) in men aged 25 to 64 years old. Screening of male inhabitants of one of Novosibirsk districts, aged 25 to 64 years, was performed within the framework of the WHO MONICA-psychosocial program in 1994. The cohort was followed up during 8 years (1994 - 2002) to determine end-points (MI). The statistical analysis was performed using SPSS- 10 software package. The relative risk (RR) of MI was evaluated using Cox proportional regressive model. Only one third of the 25 to 64-year-old male subjects with the first MI referred to their sleep as "good" whereas two thirds had sleep disturbances. The 8-year RR of MI in men aged 25 to 44 was 9.25 times higher in those whose sleep was estimated as '"poor" vs. those with "good" sleep, i. e. in this age group sleep disturbances were one of the most important MI risk factors; in 45 to 64 age group these differences were insignificant. RR of IM in men with sleep disturbances was higher in widowers, divorced men, men with low social support level, men with only primary education, working class men, and pensioners. The results demonstrate that sleep disturbances present a social problem and contribute greatly to the risk of MI in men of young age group.     

Study of myocardial infarction risk factors within the framework of the WHO Monica-psychosocial program

Three screening population studies were carried out within the framework of the WHO MONICA-psychosocial program in 1984, 1988, and 1994. The subjects of the study were male inhabitants of one of Novosibirsk districts aged 25 to 64 years. The cohort was studied during 18 years, from 1984 to 2002, using the WHO Acute Myocardial Infarction Register program. The statistical analysis was performed using SPSS-10 software package. The relative risk (RR) of myocardial infarction (MI) was estimated using Cox proportional regressive model. The greatest proportion (38.9%) of patients with MI was among men aged 45 to 54 years. Among men with MI, 58.7% had a high personal anxiety (PA) level. RR of MI was high among widowers, divorced and single men with a high PA level, in men with incomplete secondary or primary education, and men of hard or moderate physical labor. In the age group of 24 to 44, RR of MI during the first 5 and 10 years was 7.5 times higher in men with a high PA level vs. men with a medium PA level (p < 0.01). This explains the bigger number of men with MI in the group of 45 to 54 years of age.