Times Normal Levels Research Articles

P.74 Using high-field magnetic resonance spectroscopy to measure muscle glycogen in patients with McArdle disease

Glycogen plays a critical role as an energy source in skeletal muscle. McArdle disease is a recessively inherited disorder in which muscle glycogen breakdown is blocked due to myophosphorylase deficiency. The patients suffer from severe exercise intolerance marked by premature fatigue with muscle contractures and episodic rhabdomyolysis. Additionally, some patients show progressive muscular atrophy when they get older, mainly in lumbar paraspinal muscles but not in thigh or calf muscles. The cause of fat replacement in older McArdle patients is unknown but could relate to a higher glycogen accumulation in their muscles. Utilizing the high sensitivity of 13C magnetic resonance spectroscopy at 7 Tesla field strength, we wanted to quantify muscle glycogen in lumbar, thigh and calf muscles in young McArdle patients as well as healthy controls to test the hypothesis of variable glycogen content in muscles of patients with McArdle disease. Preliminary results from 5 patients and 8 controls, show increased muscle glycogen concentration in the calf (4.4 times normal levels, p = 0.002), hamstrings (2.7 times normal levels, p = 0.02) and anterior thigh compartment (3.2 times normal levels, p = 0.01), while there was no difference in the lumbar muscle glycogen content vs. healthy (p = 0.6). No clear pattern of muscle glycogen distribution was seen in neither the McArdle nor the control groups. Our results are in line with previous studies in that we see a 3-5 times increase in glycogen compared to control. Surprisingly, this is not seen in the lumbar muscle group, which is the muscle group most prone to fat replacement with age. Thus, it does not appear that a difference in glycogen concentration between muscles of McArdle patients can explain the fat replacement seen in specific muscles groups of older patients.

Impact of Comorbidities on Health-related Quality of Life in Nontransplant Eligible Patients With Newly Diagnosed Multiple Myeloma.

Impact of Comorbidities on Health-related Quality of Life in Nontransplant Eligible Patients With Newly Diagnosed Multiple Myeloma.

Investigating the utility of saliva immunoglobulins for the detection of myeloma and using myeloma proteins to clarify partition between oral and systemic immunity.

ObjectivesMyeloma is characterised by the presence of monoclonal immunoglobulin (M‐protein) and the free light chain (FLC) in blood. We investigated whether these M‐proteins and FLC are detectable in myeloma patients’ saliva to evaluate its utility for non‐invasive screening and monitoring of haematological malignancies.MethodsA total of 57 patients with monoclonal gammopathy and 26 age‐matched healthy participants provided paired serum and saliva samples for immunoglobulin characterisation and quantification.ResultsMyeloma patients had IgG or IgA M‐protein levels ranging up to five times and FLC levels up to a thousand times normal levels of polyclonal immunoglobulins. Despite these highly elevated levels, only two IgG and no IgA M‐proteins or FLC could be detected in paired saliva samples. Most patients had reduced levels of serum polyclonal immunoglobulins, but all had normal levels of salivary IgA.ConclusionsImmunoglobulin transfer from blood is not determined by levels in the systemic circulation and more likely dictated by periodontal inflammation and the integrity of the oral epithelium. Immunoglobulins secreted by bone marrow plasma cells do not substantially enter saliva, which represents a poor medium for myeloma diagnosis. These findings, along with normal salivary IgA levels despite systemic immunoparesis, support a strong partitioning of oral from systemic humoral immunity.

Association of Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) with Mortality in Patients with Coronavirus Disease 2019 (COVID-19) in Fatmawati General Hospital: A Preliminary Data

Background : COVID-19, caused by SARS-CoV-2 virus, is a novel disease that has not been previously identified. The disease may result in multiple organ impairment leading to death. Liver is also affected by this viral infection. This study aimed to investigate the association of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) with mortality rate in these patients. Method : This is a retrospective cohort study of COVID-19 patients admitted in Fatmawati General Hospital during a period of March-April, 2020. Diagnosis of COVID-19 was established from real time Polymerase chain reaction (RT PCR). Association of AST and ALT levels with mortality was analyzed by using SPSS ® version 16.0. Result s : Forty-two patients were diagnosed as confirmed case of COVID-19, 52.3% of them were male. Mean age was 54.6±12 years. Median (IQR) value of AST and ALT levels were 55(48) U/L and 39(40) U/L, respectively. AST and ALT was elevated in 71.4% and 42.9%, respectively. Increased levels of AST and ALT 2 times above the upper normal limit (UNL), >2 times ULN, and > 5 times ULN were found in 33.3% and 21.4%; 38.1% and 21.4%; 4.8% and 4.8%, respectively. Mortality was recorded in 45.1% of these confirmed cases, 50% occurred within 2 days of hospitalization. Higher mean value of AST is associated with an increased mortality risk (101 ± 147 U/L vs. 82.78 ± 173 U/L; p 0.032). Sub-analysis identified that abnormal AST >2 times above UNL has a higher mortality proportion compared with AST 2 times UNL and normal AST levels (62.5% vs. 50% vs. 16.7%; p 0.05). Mean value of ALT is not associated with mortality (p 0.479). Further sub-analysis found that in patients who succumbed to the disease, abnormal levels of AST and ALT is related to the time of death during hospitalization despite being statistically not significant. Conclusion : Mortality rate of COVID-19 in hospitalized patients remains high. Increased AST levels was significantly associated with higher mortality rate. This finding merit further investigation by incorporating larger sample size to discern the role of these factors’ contribution to mortality in COVID-19.

Liver cirrhosis with high IgG4 in a patient with, diabetes mellitus, ulcerative colitis with papillary thyroid cancer, is it all related ? which one to blame& is it time to raise awareness about IGG4 and hepatobiliary diseases

Back ground: There is possible etiological relation between high IgG4 in a patient with liver cirrhosis, ulcerative colitis, diabetes mellitus , prostatitis ,venous thrombosis and thyroid cancers and the use of immunosuppressive & biologic agents. Method: a study of patient with multiple organ involvement with persistently elevated IgG4. A 56 years old male with persistently elevated IgG4 over 2.5 times normal level, diabetic on insulin, ulcerative colitis on azathioprin & adalimumab developed deep skin pigmentation and liver enzymes elevation with portal hypertension and liver cirrhosis, azathioprine & adalimumab were stopped and golimumab started, after 3 infusions of golimumab papillary thyroid cancer developed .Total thyroidectomy followed by radio iodine after which severe sialo adenitis developed which responded to steroids. His ulcerative colitis was treated with vedolizumab with good response. liver cirrhosis progressed with bleeding varices and portal vein thrombosis with factor Leiden V mutation. Results and conclusions: High IgG4 can be related to many organs including pancreas,liver,thyroid ,small and large bowel,parotid glands ,in this patients all these were affected resulting in colitis,diabetes,liver cirrhosis and thyroid cancer and sialo adenitis. Awareness is needed on the associations with high IgG4. Conclusion: A patient with elevated IgG4 , liver cirrhosis , diabetes mellitus, ulcerative colitis developed skin pigmentation, and papillary thyroid cancer associated with persistently elevated IgG4.

0152: Is amiodarone a safe and effective alternative drug in persistant fetal tachycardias?

Persistant fetal tachycardias, especially when complicated with hydrops, are associated with a poor prognosis. Digoxin and flecaine are usually used but not always effective. Amiodarone remains frequently a last choice of treatment because of its known complications. In this retrospective study, we reviewed the use of amiodarone in patients with resistant fetal tachycardia, to determine the safety of this drug and its efficiency. Between 1986 and 2012, sixteen pregnancies admitted for fetal tachycardia were treated with amiodarone. Four had atrial flutter and twelve had supra-ventricular tachycardia. The fetuses were severe: ten fetuses (63%) had hydrops. Amiodarone was never used as a first line therapy, but as a second line therapy in 6 fetuses and as a third line therapy in 6 fetuses. Amiodarone was effective in 10 of the 16 (63%) patients and despite the presence of hydrops (efficiency was obtained in 4/6 fetuses of the non hydropic group versus 6/10 of the hydrops group, p=NS). Among mothers, two complications were noticed: mild hypothyroidism and hepatic cytolysis. Hypothyroidism was present in three patients who did not need any substitutive treatment. Hepatic cytolysis was also present in three patients but never above three times normal level. Fetuses were born at 35.8±3.2 WA, weighed 2805±579g, and five of them required oral intubation at birth. One fetal death occured (sinusal rhythm was obtained but hydrops with ventricular dysfunction persisted and a ventricular thrombus appeared). Hypothyroidism was present in six patients: three had transient hypothyroidism that resolved in two weeks, two were treated for six months and one is still treated. All children had normal neurological development. Persistant tachycardias complicated with hydrops remain a medical challenge. Amiodarone seems to be a safe and efficient alternative drug in this indication.

Efficacy of herbomineral compounds and pathya (Ayurvedic dietary regime and physical exercise) in the management of Yakṛt Roga (Non-alcoholic fatty liver disease).

Background:Nonalcoholic fatty liver disease (NAFLD) also called as hepatic steatosis is a manifestation of excessive triglyceride accumulation in the liver. NAFLD has been described by histological features ranging from simple fatty liver, nonalcoholic steatohepatitis, progressive fibrosis, and liver failure.Objective:The objective was to evaluate the effect of herbomineral drugs and pathya (Ayurvedic dietary regime and physical exercise) in the management of NAFLD.Materials and Methods:It is a randomized, retrospective, open-ended study. A total of 32 patients presenting with raised alanine transaminase (>1.5 times normal levels) combined with sonological evidence of fatty liver in the absence of any other detectable cause of liver disease were included in the study. The recruited patients were randomly divided into two groups - The patients in Group-A (n = 21) were given a combination of herbomineral drugs Ārogyavardhinī vaṭi and Triphalā Guggulu along with prescription of pathya (Ayurvedic dietary regime and physical exercise); the patients in Group-B (n = 11) were advised only pathya.Results:Group-A (combined therapy group) showed statistically significant improvement in clinical symptoms, biochemical parameters-liver function test, lipid profile, fasting blood sugar, and body mass index (P < 0.001) in comparison to Group-B (pathya group).Conclusion:Combination of herbomineral drugs along with pathya has shown promising results toward the effective management of this metabolic disorder.

SWOG 1211: Initial Report on PHASE I Trial of RVD-Elotuzumab for NEWLY Diagnosed High Risk Multiple Myeloma (HRMM)

BACKGROUND: The introduction of novel agents and proteasome inhibitors, and advances in high dose therapy administration has made an impact on the survival outcomes for MM patients. However, HRMM still remains a therapeutic challenge with poor prognosis. Even with aggressive approaches such as the Total Therapy protocols, patients with poor genomic risk have a 2-year event-free survival of ~50% (Nair et al, Blood 2010). A randomized Phase I/II trial was designed to evaluate the efficacy of adding immunotherapy into the first line for HRMM patients, comparing lenalidomide, bortezomib and dexamethasone (RVD) with or without addition of elotuzumab (Elo), a humanized monoclonal antibody that binds to SLAMF7/CS1. We are reporting on the Phase I portion of the study.PATIENTS & METHODS: The objective of Phase I was to determine the maximum tolerated dose (MTD) of RVD-Elo. Both low/standard risk MM and HRMM patients were eligible. HRMM was defined by one or more of the following: (1) poor risk genomics by the Arkansas 70-gene model, (2) translocation (14;16), translocation (14;20) and/or deletion (17p) by florescent in-situ hybridization (FISH), (3) primary plasma cell leukemia and (4) serum LDH > 2 times normal levels. The treatment consisted of induction chemotherapy for 8 cycles with RVD-Elo (lenalidomide 25 mg orally days 1-14 of every 21-day cycle; bortezomib 1.3 mg/m2 subcutaneously days 1,4,8,11; dexamethasone 20 mg orally days 1,2,4,5,8,9,11,12; elotuzumab 10 mg/kg intravenously days 1,8,15 cycles 1-2 then days 1,11 cycles 3-8) followed by dose-attenuated RVD-Elo maintenance (lenalidomide 25 mg orally days 1-14; bortezomib 1.0 mg/m2 subcutaneously days 1,8,15; dexamethasone 12 mg orally days 1,8,15; elotuzumab 10 mg/kg intravenously days 1,15) until disease relapse, progression or intolerance. Adverse events (AE) were recorded as per the NCI CTCAEv4.0.RESULTS: Eight newly diagnosed MM patients were enrolled on the Phase I run-in study. Six patients (Figure 1) were evaluable for dose limiting toxicities (DLT) during Cycle 1 as per protocol. The median age of patients was 67 years (range: 56-79 years), with 67% ≥65 years, Hgb was less than 10 g/dL in 50%, creatinine was greater than 2 mg/dL in all patients. ISS stage distribution was 17% (I), 33% (II) and 50% (III). Deletion 13 was observed in 1 patient (17%). The most common AEs (all grades) were fatigue (100%), peripheral sensory neuropathy (83%), edema (83%), lymphopenia (66%) and leukopenia (50%). The most common Grade 3 AEs were peripheral sensory neuropathy (33%), one of which was a DLT, neutropenia (17%) and thrombocytopenia (17%). One Grade 4 lymphopenia was observed. All 6 patients have completed 8 cycles of RVD-Elo induction therapy and 5 patients have completed at least 4 cycles of RVD-Elo maintenance. Overall median days on therapy per cycle were 13 days during induction and 20 days per cycle during maintenance. Dose adjustments were made in 83% of patients for bortezomib, 83% for lenalidomide and 33% for dexamethasone. There were no dose reductions for elotuzumab, although three patients had 1 event each of dose delays/missed dosing attributable to AE/SAE from RVD. Efficacy data will be released at the time that the phase II study of RVD +/- Elo is mature.Discussion/Conclusion: The RVD-Elo is a safe well-tolerated regimen for newly diagnosed MM patients without major additive AE/SAE beyond what is already known about RVD. This is the first report of the only phase I experience combining the triple-drug regimen RVD with the monoclonal antibody Elotuzumab for newly diagnosed MM.Support: NCI grants CA32102, CA38926, CA180821, CA31946, CA21076, CA180799, CA21115, CA180820 and in part by Bristol-Myers Squibb Company DisclosuresUsmani:Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma patients. Ailawadhi:Millennium: Honoraria. Shah:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Rosenzweig:Celgene: Speakers Bureau. Durie:IRC J&J: Membership on an entity’s Board of Directors or advisory committees; Celgene Corp: Expert Board Committee Other; IRC Onyx: Membership on an entity’s Board of Directors or advisory committees; DMC Millennium: Membership on an entity’s Board of Directors or advisory committees. Orlowski:Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding; JW Pharmaceutical: Research Funding; Array BioPharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees.

Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid

Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC) but excellent response is not observed in all cases. Since potential favourable effects of fibrates have been reported in short series with inconclusive results, we have carried out a pilot study to analyse the effects of bezafibrate in patients with suboptimal response to UDCA. Thirty women (age 52.3 ± 2.3 years) treated with UDCA and abnormal alkaline phosphatase (AP) levels received bezafibrate (400 mg/d) for 1 year. Changes were measured every 3 months during the study period of 12 months, 3 months after discontinuation and 3 months after resuming bezafibrate. Two patients discontinued the treatment after few days, three at 6 and one at 9 months. Bezafibrate treatment resulted in a significant decrease in AP as early as 3 months. Normalization or decrease of AP below 1.5 times normal levels was observed in 13 and 4 patients respectively. There was also a significant decrease in γ-glutamyl transferase and alanine aminotransferase, cholesterol and triglyceride levels. Bezafibrate treatment resulted in significant improvement of pruritus. A rebound in liver biochemistries and pruritus occurred upon drug discontinuation, changes which improved again after resuming bezafibrate. Response to bezafibrate was associated with lower liver stiffness and severity of cholestasis. No severe adverse effects were observed. Combination treatment of bezafibrate and UDCA is associated with marked decrease or normalization of alkaline phosphatase as early as 3 months in patients with PBC. Better biochemical response was observed in patients with early disease and lower cholestasis.

The incidence and magnitude of fibrinolytic activation in trauma patients

Trauma is a global disease, with over 2.5 million deaths annually from hemorrhage and coagulopathy. Overt hyperfibrinolysis is rare in trauma, and is associated with massive fatal injuries. Paradoxically, clinical trials suggest a much broader indication for antifibrinolytics. To determine the incidence and magnitude of fibrinolytic activation in trauma patients and its relationship to clot lysis as measured by thromboelastometry. A prospective cohort study of 303 consecutive trauma patients admitted between January 2007 and June 2009 was performed. Blood was drawn on arrival for thromboelastometry (TEM) and coagulation assays. Follow-up was until hospital discharge or death. TEM hyperfibrinolysis was defined as maximum clot lysis of > 15%. Fibrinolytic activation (FA) was determined according to plasmin-antiplasmin (PAP) complex and D-dimer levels. Data were collected on demographics, mechanism, severity of injury, and baseline vital signs. The primary outcome measure was 28-day mortality. The secondary outcome measures were 28-day ventilator-free days and 24-h transfusion requirement. Only 5% of patients had severe fibrinolysis on TEM, but 57% of patients had evidence of 'moderate' fibrinolysis, with PAP complex levels elevated to over twice normal (> 1500 μg L(-1)) without lysis on TEM. TEM detected clot lysis only when PAP complex levels were increased to 30 times normal (P < 0.001) and antiplasmin levels were < 75% of normal. Patients with FA had increased 28-day mortality as compared with those with no FA (12% vs. 1%, P < 0.001), fewer ventilator-free days, and longer hospital stay. FA occurs in the majority of trauma patients, and the magnitude of FA correlates with poor clinical outcome. This was not detected by conventional TEM, which is an insensitive measure of endogenous fibrinolytic activity.

Golden plumes: Substantial gold enrichment of oceanic crust during ridge-plume interaction

Mantle plume events are increasingly implicated as the source of gold (Au) in regions of the Earth that show a high Au endowment. However, the process of enriching oceanic crust in Au by plume activity is poorly understood and unconstrained. We present the first systematic study of Au concentrations in oceanic basalts as a function of distance from a plume center. We show that the influence of the Iceland plume on the Mid-Atlantic Ridge progressively enriches the oceanic crust in Au along the Reykjanes Ridge by as much as 13 times normal levels, over a distance of similar to 600 km, and that the enrichment can be attributed to specific plume components. This Au enrichment by the Iceland plume implies a genetic relationship between deep mantle upwelling and major gold mineralization.

Silver Toxicity With the Use of Silver-Impregnated Dressing and Wound Vacuum-Assisted Closure in an Immunocompromised Patient

Silver-containing topical agents are used to help prevent infectious complications in wound therapy. Toxicity from topical silver agent exposure was initially reported in 1975 and was clinically characterized by granulocytopenia. Currently, the data regarding potential toxicity associated with silver-impregnated devices are limited. A 23-year-old patient receiving chemotherapy for acute lymphoblastic leukemia presented with necrotizing fasciitis of the abdominal wall and scrotum from a Crohn disease-related psoas-enteric fistula. Surgical debridement of the soft-tissue and abdominal musculature was performed to the peritoneum. Silver-containing foam sponges and wound vacuum-assisted closure were applied directly to the peritoneum 2 weeks after initial debridement. Subsequently, the patient developed leukopenia, and workup revealed the serum silver level was 4 times normal level. Silver-impregnated sponges were discontinued and silver-free sponges and wound vacuum-assisted closure therapy resumed, followed by leukopenia resolution. Silver toxicity associated with routine application of silver-impregnated sponges has not been previously reported.

Impacts of shellfisheries and nutrient inputs on waterbird communities in the Wash, England

Summary 1. Overexploited fisheries threaten many species that depend on the exploited resource. Shorebird populations are in decline globally and here we describe how changing shellfishery management and nutrient inputs have had dramatic influence on waterbird communities on an internationally important wetland. 2. Cockle Cerastoderma edule and mussel Mytilus edulis fisheries conflict with shorebirds by removing prey and increasing mortality amongst non‐target benthic invertebrates. Under intense dredging pressure, evidence suggests that benthic invertebrates such as worms, with rapid growth and short‐generation times, should predominate over species such as bivalves, with slower growth and longer generation times. 3. We investigated the change in the waterbird assemblage in the Wash, eastern England, between 1981–1982 and 2002–2003. This period was characterized by heavy fishing pressure on mussels and cockles, ultimately leading to a crash in the mussel stocks. 4. During the study period, the waterbird assemblage underwent a gradual change from one dominated by those species with a high proportion of bivalves or ‘other’ prey (e.g. crustaceans, fish) in their diet to those with a higher proportion of worms. This gradual change was punctuated by major shifts, corresponding to three winters when oystercatcher Haemotopus ostralegus mortality was 5–13 times normal winter levels. 5. Oystercatcher, knot Calidris canutus and shelduck Tadorna tadorna showed the highest levels of decline. Since the last major oystercatcher mortality event in 1996–1997, the assemblage has not shifted back to that observed prior to the major crash in the mussel stock in 1992. 6. Changes in the waterbird assemblage were significantly related to mussel and cockle stock levels and, to a lesser extent, nutrient levels. Although correlative, evidence from this study indicates that fisheries caused shifts towards a waterbird community dominated by species with a high proportion of worms in their diet. 7. Synthesis and applications. Mechanical shellfisheries directly conflict with the nature conservation interest of sites holding internationally important waterbird populations. Removal of the mussel beds in the Wash led to major shifts in the waterbird assemblage, with a shift towards worm‐feeders. Setting annual quotas that provide sufficient food for shellfish‐eating birds is essential to maintain the favourable status of this and other internationally important wetlands where shellfish are exploited.

Management of chronic habits of abnormal eye rubbing

A review of the provocations and the consequences of chronic habits of abnormal rubbing indicates a range of possible adverse responses. Gentle rubbing may double intraocular pressure. However, the combination of tight eye closure and forceful rubbing may raise intraocular pressure to more than 10 times normal levels. The possibility that, in susceptible individuals, chronic habits of abnormal rubbing may lead to the development or progression of keratoconus has been extended to the possibility of rubbing related adverse responses in other diseases and conditions. The adverse consequences of rubbing appear to be active processes, in contrast to the apparent passive nature of any recovery from those responses. Avoidance of the possibility of permanent adverse changes is clearly preferable. However, advice to avoid rubbing may not be successfully followed. Education and counseling appear to be the foundations for helping patients to control chronic habits of abnormal rubbing. An instrument has been developed as the basis for patient education and counseling for this purpose. It is intended as a take-home document which might have relevance to other family members. The widening of the application of this form of patient education to all members of a family, and a wider range of conditions, may produce beneficial synergy with advantage to patients who may have the most to gain from controlling chronic habits of abnormal rubbing.

Targeted delivery of an Mecp2 transgene to forebrain neurons improves the behavior of female Mecp2-deficient mice

Rett syndrome is an X-linked neurological condition affecting almost exclusively girls that is caused by mutations of the MECP2 gene. Recent studies have shown that transgenic delivery of MeCP2 function to Mecp2-deficient male mice can improve their Rett-like behavior. However, as the brain of a Rett girl contains a mosaic of MeCP2 expressing and non-expressing neurons, and the over-expression of MeCP2 in neurons can induce a severe progressive neurological phenotype, testing whether functional rescue can be achieved by gene re-introduction strategies in a female model of Rett syndrome is warranted. To address this, we generated transgenic mice expressing an epitope-tagged Mecp2 transgene in forebrain neurons. These mice over-express MeCP2 protein at about 1.6 times normal levels in cortex and develop impaired motor behavior by 9-12 months of age. To test whether forebrain-targeted MeCP2 restoration would improve behavior in female Mecp2(-/+) mice, we crossed these transgenics with Mecp2(-/+) mice and examined the behavioral properties of the female rescue mice for 1 year. These assessments revealed that the diminished rearing activity, impaired mobility and the diminished locomotive activity of female Mecp2(-/+) mice were restored to wild-type levels in the rescue mice. These results show that improvement of Rett-like behavior can be achieved in Mecp2(-/+) females by targeted gene re-introduction without inducing deficits relating to MeCP2 over-expression.

PYTHONS PAUSE POSTPRANDIALLY

Pythons don't rely on the standard three square meals a day: in an eating regime that would finish off most animals, they go for weeks or months on end without eating, and then gorge themselves on a huge meal before their next fast. Burmese pythons cope with this cycle of extreme feeding and fasting by increasing their metabolism and their intestines' ability to absorb food after meals, shutting down the gut when it's not needed during fasting.To find out if other species of python can do the same, Brian Ott and Stephen Secor from the University of Alabama measured metabolic rate, nutrient absorption, intestine morphology and enzyme activity in five python species,ranging in size from short and stout to long and slender(p. 340). Using the pythons' oxygen consumption to measure metabolic rate, the team found that metabolic rates peaked to between 10-15 times normal levels 1.5 days after eating a delicious rodent meal, returning to normal 6-8 days later.Interested to know what changes were happening in the gut during digestion,they found that the meal increased activity in the aminopeptidase-N enzyme,which breaks down proteins, and triggered faster absorption of animo acids and glucose by the gut. The mass of the intestine also doubled, because the membranes and cells involved in absorbing food increased in mass and volume. The results show that different species of python share the ability to make the most of their enormous, yet infrequent meals, soaking up nutrients to see them through leaner times.

Prolonged Lamivudine Treatment in Patients with Chronic Active Anti-HBe–Positive Hepatitis

The efficacy of lamivudine (LAM) at 100 mg/d for 1 year in normalizing serum ALT levels and suppressing HBV DNA has been demonstrated in many studies. However, frequent relapses make long-term results modest. In the present study, we evaluated the efficacy of LAM administered for 3 years in patients with chronic active anti-HBe-positive hepatitis. Thirty-four patients with chronic active anti-HBe-positive hepatitis were treated with LAM (100 mg) once daily for 3 years. Before treatment, all patients demonstrated serum ALT levels >2 times normal levels for >6 months and HBV DNA positivity >5 pg/mL as determined by the sandwich hybridization test for nucleic acid. Both ALT and HBV DNA were monitored during therapy. After 12 months of therapy, 24 of 34 patients (70.6%) showed evidence of HBV DNA clearance and normal ALT levels; 22 of 34 (64.7%) and 19 of 34 (55.8%) patients maintained a complete response after 2 and 3 years of therapy, respectively. The long-term LAM therapy (>1 year) was not associated with an increase in the response of intially nonresponder patients. The YMDD variant emerged in 17.6% of patients in the first year, in 35.2% during the second year, and 52.9% during the third year of treatment. LAM was well tolerated during the 3-year therapy in all patients. Patients with chronic active anti-HBe-positive hepatitis demonstrated that the LAM response rate tends to decrease over time due to the emergence of YMDD variants.

An Unusual Case of Generalized Soft-Tissue Mineralization in a Suckling Foal

An atypical case of severe soft-tissue mineralization in a 3-week-old foal from a herd of Andalusian horses is described. The herd clinical history and the laboratory findings were compatible with a diagnosis of secondary hyperparathyroidism due to a mineral imbalance in the diet (low calcium and high phosphorus intake). Mares showed a marked increase in serum parathyroid hormone (PTH) approximately 10 times normal levels. Serum PTH was marginally elevated in foals. Clinical signs (unthriftiness, painful joints, lameness in one or more limbs, and stiff gait) were more pronounced in foals than in mares. Two foals died and necropsy of one of them revealed extensive soft-tissue mineralization of arterial walls and pulmonary parenchyma. Clinical signs in mares and foals resolved by 4 weeks after diet adjustment.

PREDICTION OF RENAL CONCENTRATIONS OF DEPLETED URANIUM AND RADIATION DOSE IN GULF WAR VETERANS WITH EMBEDDED SHRAPNEL

Mobilization of uranium (U) from embedded depleted uranium (DU) metal fragments in Gulf War veterans presents a unique exposure scenario for this radioactive and nephrotoxic metal. In a cohort of exposed veterans, urine U concentrations measured every two years since 1993 persistently range from 10 to over 500 times normal levels, indicating that embedded DU fragments give rise to chronic, systemic exposure to U. Health effects of this exposure are not fully known, but clinical surveillance of these soldiers continues in light of animal studies showing that U released from implanted DU pellets results in tissue accumulation of U. The biokinetic model for uranium recommended by the International Commission on Radiological Protection was used to predict kidney U concentrations and tissue radiation doses in veterans with DU shrapnel based on their urine U excretion. Results suggest that kidney U concentrations in some individuals reached their peak within six years after the war, while in others, concentrations continue to increase and are approaching 1 ppm after 10 y. These results are consistent with urine biomarker tests of renal proximal tubular cell function and cytotoxicity which have shown elevated mean urinary protein excretion indicative of functional effects in veterans with high urine U concentrations (> or =0.10 microg g(-1) creatinine). Predicted lifetime effective radiation dose from DU released to the blood for the highest exposed individual in this cohort was substantially less than the National Council on Radiation Protection (NCRP) limit for occupational exposure. These results provide further support for current health protection guidelines for DU, which are based on the metal's chemical rather than its radiological toxicity. In light of the potential for continued accumulation of U in the kidney to concentrations approaching the traditional guidance level of 3 ppm U, these results indicate the need for continued surveillance of this population for evidence of developing renal dysfunction.

Glial and neuronal connexin expression patterns in the rat spinal cord during development and following injury

Spinal cord injury induces a complex cascade of degenerative and remodeling events evolving over time. The possible roles of changed intercellular communication via gap junctions after spinal cord injury (SCI) have remained relatively unexplored. We investigated the temporospatial expression patterns of gap junctional genes and proteins, connexin 43 (Cx43), Cx36, and Cx32, by in situ hybridization and immunohistochemistry in the rat neonatal, adult normal, and adult injured spinal cord. Cx36 was strongly expressed in immature neurons, and levels declined markedly during development, whereas Cx43 and Cx32 persisted throughout adulthood. After a complete transection of the adult spinal cord, the levels of Cx43 mRNA and protein were up-regulated within hours, especially in gray matter rostral to the lesion, reaching over three times normal levels at 4 weeks postinjury. Cx43 immunoreactivity was seen primarily in astrocytes and rarely in microglia. In contrast, Cx36 and Cx32 mRNA and proteins were relatively sparse and unchanged after spinal cord injury along the entire axis of the spinal cord. Cx43 is the most abundant gap junctional protein in the adult CNS and has been shown to form channels between astrocytes as well as between astrocytes and oligodendrocytes. Long-term up-regulation of Cx43 in reactive astrocytes may be one critical component in the rearrangement of the local astroglial network following SCI.