fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/ fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 ( atf-6 ), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity- promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

Hereditary neuropathy with liability to pressure palsies: description of seven patients without known family history.

OBJECTIVES: Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited disorder resulting in a polyneuropathy with particular involvement at sites of entrapment, and is often underdiagnosed or misdiagnosed. We report findings on seven patients referred for evaluation of focal mononeuropathies or polyneuropathies of undetermined etiology, in whom we established a diagnosis of HNPP. MATERIALS AND METHODS: We retrospectively reviewed clinical, electrophysiological and laboratory data for patients diagnosed with HNPP over a 4-year period at our institution. RESULTS: All patients had transient or recurrent neurological symptoms, some with residual deficits. No patients had a family history of any neuropathy. Electrodiagnostic studies revealed abnormal conduction findings at symptomatic and asymptomatic sites. Testing for the Peripheral Myelin Protein (PMP22) deletion was positive in all patients. CONCLUSIONS: A high index of clinical suspicion and thorough electrodiagnostic evaluation can lead to correct diagnosis of HNPP, despite the absence of a positive family history.

Blockade by ruthenium red of tissue factor-initiated coagulation.

The ability of ruthenium red (RuR) to inhibit tissue factor (TF)-initiated blood coagulation was demonstrated at the protein and cellular levels as well as in human plasma. In a single-stage clotting assay, RuR concentration-dependently inhibited rabbit brain thromboplastin (rbTF)-induced coagulation and offset bacterial endotoxin (LPS)-induced monocytic TF (mTF) hypercoagulation; the IC(50)s were estimated at 7.5 and 12.3 microM, respectively. A 15-min preincubation of RuR with rbTF or monocyte suspension resulted in the pronounced inhibition with a significantly lowered IC(50) at 1.8 or 7.7 microM for rbTF or mTF procoagulation, respectively. The differences in IC(50)s between rbTF and mTF without or with the preincubation indicated that TF was a primary target for RuR action. The effect of RuR on the physiological function of TF in FVII activation was demonstrated by the proteolytic cleavage of FVII zymogen to its active forms of serine protease on Western blotting analyses. RuR readily blocked TF-catalyzed FVII activation (diminished FVIIa formation), thus down regulating the initiation of blood coagulation. Inclusion of RuR into human plasma samples in vitro significantly prolonged prothrombin time, indicating the depressed coagulation. FVII activity was inhibited by 30 - 60% depending on the dose; as a result, FX activity also decreased. However, RuR showed no effect on thrombin time. Thus, RuR inhibited FVII activation to block the initiation of coagulation.

Endogenous creatinine clearance during pregnancy. Part I. Methodologic considerations.

The effect of noncreatinine chromogens on the endogenous creatinine clearance (ECC) during pregnancy was investigated. It was found that these chromogens measured as plasma "creatinine" cause a significant reduction in the ECC value. This fact should be considered when the ECC value is used to evaluate renal function during pregnancy.

Endogenous creatinine clearance during pregnancy. II. Variations in normal standards based on methodology.

A comparison of the endogenous creatinine clearance (ECC) values by using creatinine levels measured by the autoanalyzer and the modified Jaffe reaction using Lloyd's reagent was performed in 108 normal ambulatory pregnant women at various stages of gestation. The mean ECC was found to be significantly lower when the former method was employed except between 39 and 41 weeks when the values became similar. The mean ECC when calculated from the autoanalyzer results did not vary during pregnancy since serum creatinine by this method remained fairly constant. The difference in serum creatinine level between the two methods observed during pregnancy was absent in the nonpregnant state.

Novel anticoagulant activity of polybrene: inhibition of monocytic tissue factor hypercoagulation following bacterial endotoxin induction.

The enhanced extrinsic coagulation in response to inflammation could contribute to disseminated intravascular coagulation, often manifesting cardiovascular complications. The complex mechanism remains unclear. Nor is the effective anticoagulation well established. The search for arresting hypercoagulation is of antithrombotic relevance. The ability of polybrene (PB) to inhibit tissue factor (TF)-initiated extrinsic blood coagulation was demonstrated at the protein and cellular levels as well as in human plasma samples. In a single-stage clotting assay, PB dose-dependently offset bacterial endotoxin (lipopolysaccharide)-induced monocytic TF (mTF) hypercoagulation and inhibited rabbit brain thromboplastin (rbTF) procoagulation. Consistent with these findings, the significantly prolonged prothrombin time indicated the depressed extrinsic coagulation by PB. However, PB showed no effect on thrombin time. We dissected the extrinsic pathway to further determine the inhibitory site(s) of PB. A two-stage chromogenic assay monitoring S-2288 hydrolysis showed that PB readily blocked mTF-dependent or rbTF-dependent FVII activation, which was verified by the diminished activated factor VII (FVIIa) formation derived from the proteolytic cleavage of its zymogen factor VII on Western blotting analyses. PB had no effect on FVIIa and activated factor X amidolytic activity. Nor was the dissected TF/FVIIa-catalyzed factor X activation affected. In conclusion, the preferential downregulation of factor VII activation was responsible for the depressed extrinsic coagulation. PB could present a novel anticoagulant antagonizing the extrinsic hypercoagulation for the prevention of thrombotic complication following sepsis and inflammations.

Fetal supraventricular tachycardia: a case of (intermittent) atrial flutter.

Fetal tachycardia of "supraventricular" origin is uncommon. The authors present a patient with fetal ascites and atrial flutter. A review of the pertinent literature is included.

Pregnancy outcome at greater than or equal to 20 weeks' gestation in women in their 40s. A case-control study.

The obstetric performance of 166 women in their 40s who delivered during a one-year period at greater than or equal to 20 weeks' gestation was compared to that of a cohort of controls younger than 40. Medical complications--diabetes, chronic hypertension and antepartum bleeding--occurred more frequently in the older patients. They had a threefold increase in antepartum hospital admissions over the controls (23.5% vs. 7.8%). Both groups had the same perinatal mortality rate, 18/1,000, and their newborns had similar incidences of neonatal complications except for a higher frequency of major and minor congenital anomalies in the study group (16% vs. 8.4%). The older patients had a longer second stage of labor. Older nulliparas had a higher incidence of premature deliveries and cesarean sections than did their controls. The outcome of pregnancy in this age group is affected by multiple confounding variables; medical complications, parity and age play major roles.

Segmental epidural analgesia in labor: a matched control study.

The effects of epidural analgesia, given during the first stage of labor, on the course of labor, mode of delivery, and fetal outcome were evaluated in 43 matched controlled patients. Both stages of labor were prolonged, more forceps were applied, and more patients needed oxytocin augmentation for a longer period in the epidural group. Cesarean section was associated also with the use of epidural analgesia, owing to failure to progress. Fetal outcome was similar in both groups as judged by Apgar scores. Patients who elect this mode of pain relief in labor should be made aware that these side effects can be expected.

Successful pregnancy in a woman with a left ventricular cardiac aneurysm. A case report.

Ventricular cardiac aneurysms associated with pregnancy are extremely rare. The effects of one on the other are not known. The pathophysiology of cardiac aneurysms as known in the nonpregnant state combined with the physiologic cardiovascular adjustments of pregnancy can be suspected of compromising the welfare of the pregnant patient. We recently treated a 21-year-old pregnant patient with a post-myocardial-infarction left ventricular cardiac aneurysm. The outcome was successful.

Long-term plasmapheresis therapy is effective and safe in children with chronic relapsing dysimmune polyneuropathy.

Since childhood, two persons, a boy age 12 and a girl age 24 years, with chronic relapsing dysschwannian neuropathy causing severe limb weakness have been maintained on frequent plasmapheresis for more than 8-1/2 and 9 years respectively. They are totally dependent on it. Onset of disease was at ages 2-1/2 and 9 years. Both patients had had major relapses, some requiring ventilatory support, despite continued maximally-tolerated pharmacologic antidysimmune treatment. Plasmapheresis was started in August 1980 and December 1979, respectively. The current schedule is a set of 3 in one week at eight-week intervals for patient 1 and twice every 7-10 days for patient 2. They have had more than 330 and more than 1,100 phereses respectively. Since beginning phereses, neither has had a major relapse, and both are functional in their daily life as students, although with slight and moderate residual weakness respectively. The dependence of these 2 patients on regular pheresis for the last 8-1/2 and 9 years proves its efficacy and safety in children. Long-term maintenance pheresis may be beneficial in patients with other forms of chronic dysimmune neuropathy.

[Reconstruction of the penile skin in Fourier's gangrene: the use of a helical skin graft]. / La reconstruction du fourreau de la verge dans la maladie de Fournier: utilisation d'une greffe cutanée en hélice.

The emergency treatment of Fournier's and perineal gangrene is now well defined and is based on excision of the necrotic tissues and broad spectrum antibiotics combined with hyperbarid oxygen therapy and symptomatic resuscitation measures. However, several procedures have been described for the reconstruction of the excised zones. In the light of one case of Fournier's gangrene, the authors evaluate reconstruction of the penile skin by means of a helical split-skin graft. With a follow-up of one year, the morphological and functional result was excellent. The patient has normal erection and the suture line does not contain any retractile adhesions. The authors therefore consider that this simple, but little known procedure should be part of the urologist's therapeutic arsenal for reconstruction of the penile skin.

Long-term safety and tolerability of oxcarbazepine in painful diabetic neuropathy.

BACKGROUND: Painful diabetic neuropathy is a common complication of diabetes and often resistant to treatment with standard analgesics. Treatment of diabetic neuropathy with antiepileptic drugs may provide pain relief. AIM: To evaluate the long-term safety and tolerability of oxcarbazepine in two studies investigating the treatment of diabetic neuropathy. OBJECTIVES: Patients with diabetes and a history of neuropathic pain were included. Study 1 was a multicenter, open-label study comprising a screening and 12-month treatment phase. Study 2 was a multicenter, open-label extension to a double-blind, randomized study. Oxcarbazepine was initiated at 300 mg/day and titrated over 4 weeks to tolerability or a maximum dose of 900 mg b.i.d. Safety was assessed by monitoring adverse events (AEs), serious AEs (SAEs), hematology, blood chemistry, urinalysis values, and vital signs. RESULTS: Adverse events were most frequently reported in the nervous and gastrointestinal systems; 20.5% and 21.6% of patients withdrew because of AEs in study 1 and study 2, respectively. SAEs were reported in 13.7% and 14.4% of patients in study 1 and study 2, respectively. CONCLUSIONS: Long-term treatment with oxcarbazepine is generally well tolerated in patients with painful diabetic neuropathy. Rapid titration of oxcarbazepine may be responsible for discontinuations resulting from AEs during early stages of treatment.

Morphologic changes in the renal tract in pregnancy.

The morphology of the urinary tract is altered considerably during gestation. Changes occur as early as the first trimester and increase as pregnancy progresses. The edema and hyperemia that occur in the bladder along with its decreased tone predispose the patient to asymptomatic bacteriuria. The bacteria can then be transmitted to the ureters via the vesicoureteral reflux. The increase in urinary volume in the ureteropelvic system enhances the growth of the organisms and hence is thought to be the major cause of the increased incidence of pyelonephritis in pregnancy. The morphologic alterations regress dramatically as pregnancy is terminated and reach prepregnancy status at most by the third month post partum, a fact of which clinicians should be aware when interpreting diagnostic test results.

Multifocal motor neuropathy with conduction block misdiagnosed as multiple entrapment neuropathies.

We describe a 58-year-old male with a few years history of multifocal weakness in the upper limbs with minimal to absent sensory complaints. He was diagnosed as having multiple compressive neuropathies, which required repeated decompressive surgeries. Electrodiagnostic studies prior to diagnosis were limited to a few nerves, evaluating only distal segments. Because of delay in making the diagnosis, his condition progressed, and possibly because of the unnecessary surgeries, he developed atrophy in some muscles, which resulted in significant motor disability. He was later diagnosed as having multifocal motor neuropathy with conduction block and has partially responded to intravenous immunoglobulin therapy.

Premature rupture of the membranes before 28 weeks: conservative management.

The maternal and fetal outcomes of 70 consecutive singleton pregnancies with prolonged premature rupture of the membranes before 28 weeks, which were managed expectantly, were evaluated; 58.6% of the mothers developed chorioamnionitis and 13% postpartum endomyometritis. No long-term maternal sequelae were noted. None of the 22 infants born before 25 weeks survived the neonatal period. The weights of the 35 surviving infants ranged between 800 and 4100 gm. Only 29.4% of the 17 infants with long-term follow-up were both physically and developmentally normal at 6 months of age or more.

Bilateral phrenic neuropathy as a presenting feature of multifocal motor neuropathy with conduction block.

Diaphragmatic paralysis has previously been reported as a result of diverse pathologic processes involving the peripheral nervous system. We report the clinical history, physical findings, and antibody profile of an atypical case of multifocal motor neuropathy with conduction block initially presenting with respiratory failure secondary to bilateral phrenic neuropathy.