Late-onset manifestation of antenatal Bartter syndrome as a result of residual function of the mutated renal Na+-K+-2Cl- co-transporter

Genetic defects of the Na+-K+-2Cl- (NKCC2) sodium potassium chloride co-transporter result in severe, prenatal-onset renal salt wasting accompanied by polyhydramnios, prematurity, and life-threatening hypovolemia of the neonate (antenatal Bartter syndrome or hyperprostaglandin E syndrome). Herein are described two brothers who presented with hyperuricemia, mild metabolic alkalosis, low serum potassium levels, and bilateral medullary nephrocalcinosis at the ages of 13 and 15 yr. Impaired function of sodium chloride reabsorption along the thick ascending limb of Henle's loop was deduced from a reduced increase in diuresis and urinary chloride excretion upon application of furosemide. Molecular genetic analysis revealed that the brothers were compound heterozygotes for mutations in the SLC12A1 gene coding for the NKCC2 co-transporter. Functional analysis of the mutated rat NKCC2 protein by tracer-flux assays after heterologous expression in Xenopus oocytes revealed significant residual transport activity of the NKCC2 p.F177Y mutant construct in contrast to no activity of the NKCC2-D918fs frameshift mutant construct. However, coexpression of the two mutants was not significantly different from that of NKCC2-F177Y alone or wild type. Membrane expression of NKCC2-F177Y as determined by luminometric surface quantification was not significantly different from wild-type protein, pointing to an intrinsic partial transport defect caused by the p.F177Y mutation. The partial function of NKCC2-F177Y, which is not negatively affected by NKCC2-D918fs, therefore explains a mild and late-onset phenotype and for the first time establishes a mild phenotype-associated SLC12A1 gene mutation.

A Spanish founder mutation in the chloride channel gene, CLCNKB, as a cause of atypical Bartter syndrome in adult age

BACKGROUND: Mutations in the chloride channel gene, CLCNKB, usually cause classic Bartter syndrome (cBS) or a mixed Bartter-Gitelman phenotype in the first years of life. METHODS: We report an adult woman with atypical BS caused by a homozygous missense mutation, A204T, in the CLCNKB gene, which has previously been described as the apparently unique cause of cBS in Spain. RESULTS: The evaluation of this patient revealed an overlap of phenotypic features ranging from severe biochemical and systemic disturbances typical of cBS to scarce symptoms and diagnosis in the adult age typical of Gitelman syndrome. The tubular disease caused a dramatic effect on mental, growth and puberal development leading to low IQ, final short stature and abnormal ovarian function. Furthermore, low serum PTH concentrations with concomitant nephrocalcinosis and normocalcaemia were observed. Both ovarian function and serum PTH levels were normalized after treatment with cyclooxygenase inhibitors. CONCLUSIONS: The present report confirms a weak genotype-phenotype correlation in patients with CLCNKB mutations and supports the founder effect of the A204T mutation in Spain. In our country, the genetic diagnosis of adult patients with hereditary hypokalaemic tubulopathies should include a screening of A204T mutation in the CLCNKB gene.

Bacterial profile and burden of periodontal infection in subjects with a diagnosis of acute coronary syndrome

BACKGROUND: Periodontitis has been identified as a potential risk factor in cardiovascular diseases. It is possible that the stimulation of host responses to oral infections may result in vascular damage and the inducement of blood clotting. The aim of this study was to assess the role of periodontal infection and bacterial burden as an explanatory variable to the activation of the inflammatory process leading to acute coronary syndrome (ACS). METHODS: A total of 161 consecutive surviving cases admitted with a diagnosis of ACS and 161 control subjects, matched with cases according to their gender, socioeconomic level, and smoking status, were studied. Serum white blood cell (WBC) counts, high- and low-density lipoprotein (HDL/LDL) levels, high-sensitivity C-reactive protein (hsC-rp) levels, and clinical periodontal routine parameters were studied. The subgingival pathogens were assayed by the checkerboard DNA-DNA hybridization method. RESULTS: Total oral bacterial load was higher in the subjects with ACS (mean difference: 17.4x10(5); SD: 10.8; 95% confidence interval [CI]: 4.2 to 17.4; P<0.001), and significant for 26 of 40 species including Porphyromonas gingivalis, Tannerella forsythensis, and Treponema denticola. Serum WBC counts, hsC-rp levels, Streptococcus intermedius, and Streptococcus sanguis, were explanatory factors to acute coronary syndrome status (Nagelkerke r2=0.49). CONCLUSION: The oral bacterial load of S. intermedius, S. sanguis, Streptococcus anginosus, T. forsythensis, T. denticola, and P. gingivalis may be concomitant risk factors in the development of ACS.

Stewart-Treves syndrome: MR imaging of a postmastectomy upper-limb chronic lymphedema with angiosarcoma

The rare occurrence of angiosarcoma in postmastectomy upper-limb lymphedema with magnetic resonance (MR) imaging is discussed. Unfamiliarity with this aggressive vascular tumor and its harmless appearance often leads to delayed diagnosis. Angiosarcoma complicating chronic lymphedema may be low in signal intensity on T2-weighting and short tau inversion recovery (STIR) imaging reflecting the densely cellular, fibrous stroma, and sparsely vascularized tumor histology. Additional administration of intravenous contrast medium revealed significant enhancement of the tumorous lesions. Awareness of angiosarcoma and its MR imaging appearance in patients with chronic lymphedema may be a key to early diagnosis or allow at least inclusion in the differential diagnosis.

Generic detection of coronaviruses and differentiation at the prototype strain level by reverse transcription-PCR and nonfluorescent low-density microarray

A nonfluorescent low-cost, low-density oligonucleotide array was designed for detecting the whole coronavirus genus after reverse transcription (RT)-PCR. The limit of detection was 15.7 copies/reaction. The clinical detection limit in patients with severe acute respiratory syndrome was 100 copies/sample. In 39 children suffering from coronavirus 229E, NL63, OC43, or HKU1, the sensitivity was equal to that of individual real-time RT-PCRs.

Nutrition in clinical practice-the refeeding syndrome: illustrative cases and guidelines for prevention and treatment

The refeeding syndrome is a potentially lethal complication of refeeding in patients who are severely malnourished from whatever cause. Too rapid refeeding, particularly with carbohydrate may precipitate a number of metabolic and pathophysiological complications, which may adversely affect the cardiac, respiratory, haematological, hepatic and neuromuscular systems leading to clinical complications and even death. We aimed to review the development of the refeeding syndrome in a variety of situations and, from this and the literature, devise guidelines to prevent and treat the condition. We report seven cases illustrating different aspects of the refeeding syndrome and the measures used to treat it. The specific complications encountered, their physiological mechanisms, identification of patients at risk, and prevention and treatment are discussed. Each case developed one or more of the features of the refeeding syndrome including deficiencies and low plasma levels of potassium, phosphate, magnesium and thiamine combined with salt and water retention. These responded to specific interventions. In most cases, these abnormalities could have been anticipated and prevented. The main features of the refeeding syndrome are described with a protocol to anticipate, prevent and treat the condition in adults.

Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease in children, is associated with obesity and insulin resistance. However, the relationship between NAFLD and cardiovascular risk factors in children is not fully understood. The objective of this study was to determine the association between NAFLD and the presence of metabolic syndrome in overweight and obese children. METHODS AND RESULTS: This case-control study of 150 overweight children with biopsy-proven NAFLD and 150 overweight children without NAFLD compared rates of metabolic syndrome using Adult Treatment Panel III criteria. Cases and controls were well matched in age, sex, and severity of obesity. Children with NAFLD had significantly higher fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure than overweight and obese children without NAFLD. Subjects with NAFLD also had significantly lower high-density lipoprotein cholesterol than controls. After adjustment for age, sex, race, ethnicity, body mass index, and hyperinsulinemia, children with metabolic syndrome had 5.0 (95% confidence interval, 2.6 to 9.7) times the odds of having NAFLD as overweight and obese children without metabolic syndrome. CONCLUSIONS: NAFLD in overweight and obese children is strongly associated with multiple cardiovascular risk factors. The identification of NAFLD in a child should prompt global counseling to address nutrition, physical activity, and avoidance of smoking to prevent the development of cardiovascular disease and type 2 diabetes.

Transient apical ballooning syndrome--clinical characteristics, ballooning pattern, and long-term follow-up in a Swiss population

BACKGROUND: Transient apical ballooning syndrome (TABS) or Takotsubo cardiomyopathy mimics acute ST-elevation myocardial infarction, but is considered to have a good prognosis with only moderate elevation of myocardial enzymes and full recovery of left ventricular function. Although it is increasingly reported, its exact incidence, clinical presentation, and prognosis in non-Asian populations remain largely unknown. OBJECTIVE: To describe the clinical characteristics and long-term follow-up of patients who presented with TABS at our institution over a 3 year-period. METHODS: Patients were retrospectively retrieved from our local database. Patient charts were carefully reviewed and the diagnosis of TABS was based on the Mayo Clinic diagnostic criteria. Moreover, psychosocial stress or gastrointestinal disease was recorded. RESULTS: During the study period, 13,715 coronary angiographies were performed at our institution, including 2459 patients presenting with an acute coronary syndrome (ACS). Forty-one TABS were diagnosed, which represents an incidence of 1.7% of ACS-patients and 0.3% of all coronary angiographies performed, respectively. Mean age was 65 years, with 85% women. Clinical presentations included chest pain, dyspnoea, and cardiogenic shock. A preceding psychological or physical condition perceived as "stress" was reported in 61%. At a mean follow-up of 675+/-288 days, none of the patients died of cardiac causes, but two patients had a recurrence of symptoms. CONCLUSIONS: This is the largest cohort of TABS patients reported out of Europe so far. The good overall prognosis and low likelihood of recurrence were confirmed.

Acute respiratory distress syndrome secondary to antisynthetase syndrome is reversible with tacrolimus

Polymyositis and interstitial lung diseases, predominantly nonspecific interstitial pneumonia (NSIP), are known to be frequent in antisynthetase syndrome, where anti-aminoacyl-tRNA synthetase antibodies are often identified. An unusual case of acute respiratory distress syndrome, secondary to such proven NSIP of cellular type with predominant CD8 lymphocytes, is described herein. The patient described in the present case study initially had a poor recovery with high dose of steroids, but this was followed by a good improvement after the prescription of tacrolimus and a low dose of prednisone. A precise diagnosis in similar circumstances may be life-saving, allowing the successful application of new immunosuppressants.

Evidence that anti-muscarinic antibodies in Sjögren's syndrome recognise both M3R and M1R

Inhibitory anti-muscarinic receptor type 3 (M3R) antibodies may contribute to the pathogenesis of Sjögren's syndrome (SS), and putative anti-M3R blocking antibodies in intravenous immunoglobulin (IVIg) have been suggested as a rationale for treatment with IVIg. We investigated the presence of subtype-specific anti-MR autoantibodies in healthy donor and SS sera using MR-transfected whole-cell binding assays as well as M1R and M3R peptide ELISAs. Control antibodies against the second extracellular loop of the M3R, a suggested target epitope, were induced in rabbits and found to be cross-reactive on the peptides M3R and M1R. The rabbit antibodies had neither an agonistic nor an antagonistic effect on M3R-dependent ERK1/2 signalling. Only one primary SS (out of 5 primary SS, 2 secondary SS and 5 control sera) reacted strongly with M3R transfected cells. The same SS serum also reacted strongly with M1R and M2R transfectants, as well as M1R and two different M3R peptides. Strong binding to M1R and low-level activities against M3R peptides were observed both in SS and control sera. IVIg showed a strong reactivity against all three peptides, especially M1R. Our results indicate that certain SS individuals may have antibodies against M1R, M2R and M3R. Our results also suggest that neither the linear M3R peptide nor M3R transfectants represent suitable tools for discrimination of pathogenic from natural autoantibodies in SS.

Outcome indicators for vitrectomy in Terson syndrome

PURPOSE: There is no general agreement on the best indication and timing of vitrectomy in patients suffering from Terson syndrome. Therefore, we reviewed our cases in order to assess factors interfering with the functional outcome and complication rates after vitrectomy. METHODS: In this retrospective consecutive case series, the records from all patients undergoing vitrectomy for Terson syndrome between 1975 and 2005 were evaluated. RESULTS: Thirty-seven patients (45 eyes) were identified, 36 of whom (44 corresponding eyes) were eligible. The best-corrected visual acuity (BCVA) at first and last presentation was 0.07 +/- 0.12 and 0.72 +/- 0.31, respectively. Thirty-five eyes (79.5%) achieved a postoperative BCVA of > or = 0.5; 26 (59.1%) eyes achieved a postoperative BCVA of > or = 0.8. Patients operated on within 90 days of vitreous haemorrhage achieved a better final BCVA than those with a longer latency (BCVA of 0.87 +/- 0.27 compared to 0.66 +/- 0.31; P = 0.03). Patients younger than 45 years of age achieved a better final BCVA than older patients (0.85 +/- 0.24 compared to 0.60 +/- 0.33; P = 0.006). Retinal detachment developed in four patients between 6 and 27 months after surgery. Seven patients (16%) required epiretinal membrane peeling and seven cataract surgery. CONCLUSION: Ninety-eight per cent of our patients experienced a rapid and persisting visual recovery after removal of a vitreous haemorrhage caused by Terson syndrome. A shorter time between occurrence of vitreous haemorrhage and surgery as well as a younger patient age are predictive of a better outcome. Generally, the surgical risk is low, but complications (namely retinal detachment) may occur late after surgery.

A novel mutation of the epsilon-sarcoglycan gene in a Chinese family with myoclonus-dystonia syndrome

In a Chinese myoclonus-dystonia syndrome (MDS) family presented with a phenotype including a typical MDS, cervical dystonia, and writer's cramp, genetic analyses revealed a novel 662 + 1insG heterozygous mutation in exon 5 in the epsilon-sarcoglycan (SGCE) gene, leading to a frameshift with a down stream stop codon. Low SGCE mRNA levels were detected in the mutation carriers by real-time PCR, suggesting that the nonsense mutation might interfere with the stability of SGCE mRNA. This is the first report on Chinese with a SGCE mutation leading to MDS. Our data support the fact that same mutation of SGCE gene can lead to a varied phenotype, even in the same family.

A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome

BACKGROUND: The Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) gene fusion is a common cause of chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES), and patients suffering from this particular subgroup of CEL/HES respond to low-dose imatinib therapy. However, some patients may develop imatinib resistance because of an acquired T674I mutation, which is believed to prevent drug binding through steric hindrance. METHODS: In an imatinib resistant FIP1L1-PDGFRA positive patient, we analyzed the molecular structure of the fusion gene and analyzed the effect of several kinase inhibitors on FIP1L1-PDGFRA-mediated proliferative responses in vitro. RESULTS: Sequencing of the FIP1L1-PDGFRA fusion gene revealed the occurrence of a S601P mutation, which is located within the nucleotide binding loop. In agreement with the clinical observations, imatinib did not inhibit the proliferation of S601P mutant FIP1L1-PDGFRA-transduced Ba/F3 cells. Moreover, sorafenib, which has been described to inhibit T674I mutant FIP1L1-PDGFRA, failed to block S601P mutant FIP1L1-PDGFRA. Structural modeling revealed that the newly identified S601P mutated form of PDGFRA destabilizes the inactive conformation of the kinase domain that is necessary to bind imatinib as well as sorafenib. CONCLUSIONS: We identified a novel mutation in FIP1L1-PDGFRA resulting in both imatinib and sorafenib resistance. The identification of novel drug-resistant FIP1L1-PDGFRA variants may help to develop the next generation of target-directed compounds for CEL/HES and other leukemias.

Bacterial phenotype variants in group B streptococcal toxic shock syndrome

We conducted genetic and functional analyses of isolates from a patient with group B streptococcal (GBS) necrotizing fasciitis and toxic shock syndrome. Tissue cultures simultaneously showed colonies with high hemolysis (HH) and low hemolysis (LH). Conversely, the HH and LH variants exhibited low capsule (LC) and high capsule (HC) expression, respectively. Molecular analysis demonstrated that the 2 GBS variants were of the same clonal origin. Genetic analysis found a 3-bp deletion in the covR gene of the HH/LC variant. Functionally, this isolate was associated with an increased growth rate in vitro and with higher interleukin-8 induction. However, in whole blood, opsonophagocytic and intracellular killing assays, the LH/HC phenotype demonstrated higher resistance to host phagocytic killing. In a murine model, LH/HC resulted in higher levels of bacteremia and increased host mortality rate. These findings demonstrate differences in GBS isolates of the same clonal origin but varying phenotypes.

Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis

OBJECTIVES To synthesise the available evidence on pharmacological and non-pharmacological interventions recommended for fibromyalgia syndrome (FMS). METHODS Electronic databases including MEDLINE, PsycINFO, Scopus, the Cochrane Controlled Trials Registry and the Cochrane Library were searched for randomised controlled trials comparing any therapeutic approach as recommended in FMS guidelines (except complementary and alternative medicine) with control interventions in patients with FMS. Primary outcomes were pain and quality of life. Data extraction was done using standardised forms. RESULTS 102 trials in 14 982 patients and eight active interventions (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors (SNRIs), the gamma-amino butyric acid analogue pregabalin, aerobic exercise, balneotherapy, cognitive behavioural therapy (CBT), multicomponent therapy) were included. Most of the trials were small and hampered by methodological quality, introducing heterogeneity and inconsistency in the network. When restricted to large trials with ≥100 patients per group, heterogeneity was low and benefits for SNRIs and pregabalin compared with placebo were statistically significant, but small and not clinically relevant. For non-pharmacological interventions, only one large trial of CBT was available. In medium-sized trials with ≥50 patients per group, multicomponent therapy showed small to moderate benefits over placebo, followed by aerobic exercise and CBT. CONCLUSIONS Benefits of pharmacological treatments in FMS are of questionable clinical relevance and evidence for benefits of non-pharmacological interventions is limited. A combination of pregabalin or SNRIs as pharmacological interventions and multicomponent therapy, aerobic exercise and CBT as non-pharmacological interventions seems most promising for the management of FMS.