Permanent Reversal Research Articles

Intra-amniotic Delivery of CFTR-expressing Adenovirus Does Not Reverse Cystic Fibrosis Phenotype in Inbred CFTR-knockout Mice

Due to its early onset and severe prognosis, cystic fibrosis (CF) has been suggested as a candidate disease for in utero gene therapy. In 1997, a study was published claiming that to how transient prenatal expression of CF transmembrane conductance regulator (CFTR) from an in utero-injected adenovirus vector could achieve permanent reversal of the CF intestinal pathology in adult CF knockout mice, despite the loss of CFTR transgene expression by birth. This would imply that the underlying cause of CF is a prenatal defect for which lifelong cure can be achieved by transient prenatal expression of CFTR. Despite criticism at the time of publication, no independent verification of this contentious finding has been published so far. This is vital for the development of future therapeutic strategies as it may determine whether CF gene therapy should be performed prenatally or postnatally. We therefore reinvestigated this finding with an identical adenoviral vector and a knockout CF mouse line (Cftr(tmlCam)) with a completely inbred genetic background to eliminate any effects due to genetic variation. After delivery of the CFTR-expressing adenovirus to the fetal mouse, both vector DNA and transgenic CFTR expression were detected in treated animals postpartum but statistically no significant difference in survival was observed between the Cftr(-/-) mice treated with the CFTR-adenovirus and those treated with the control vector.

Sustained Arc/Arg3.1 Synthesis Controls Long-Term Potentiation Consolidation through Regulation of Local Actin Polymerization in the Dentate GyrusIn Vivo

New gene expression is necessary for long-term potentiation (LTP) consolidation, yet roles for specific activity-induced mRNAs have not been defined. Here we probed the dynamic function of activity-induced Arc (activity-regulated cytoskeletal-associated protein)/Arg3.1 (activity-regulated gene 3.1 protein homolog) mRNA using brief, local infusions of antisense (AS) oligodeoxynucleotides at multiple time points during dentate gyrus LTP in vivo. Surprisingly, early Arc synthesis is necessary for early expression of LTP, whereas sustained synthesis is required to generate stably modified synapses. AS application 2 h after LTP induction results in a rapid and permanent reversal of LTP. This reversal is associated with rapid knockdown of upregulated Arc, dephosphorylation of actin depolymerization factor/cofilin, and loss of nascent filamentous actin (F-actin) at synaptic sites. Infusion of the F-actin stabilizing drug jasplakinolide during LTP maintenance blocks the ability of AS to reverse LTP. These results couple activity-induced expression of Arc to expansion of the actin cytoskeleton underlying enduring LTP. Furthermore, Arc synthesis is required for both the induction and consolidation of LTP elicited by local BDNF infusion, thus identifying Arc as a key molecular effector of BDNF in synaptic plasticity.

Permanent Reversal of Diabetes in NOD Mice

We disagree with how J. Nishio et al. ([1][1]) represent our published data on the permanent reversal of type 1 diabetes in NOD mice ([2][2]). Nishio et al. state ([1][1]) that “a FCA alone control was not included in the report by Kodama et al. ” ([3][3]). Further, in their response to our

Electric-Field-Induced Chirality Flipping in Smectic Liquid Crystals: The Role of Anisotropic Viscosity

We demonstrate the homogeneous and permanent reversal of the chirality of a condensed phase by an applied electric field. Tilted chiral smectic layers exhibit a coupled polarization density and molecular orientation fields which reorient about the layer normal as couple of fixed handedness in response to small applied electric fields. Experiments on some bent-core smectics show that above a threshold field the induced rotation can occur instead about the molecular long axis and that, as a result, the handedness of the phase can be flipped. The effect is quantitatively described by a nonequilibrium dissipative model of chiral smectic dynamics with anisotropic rotational viscosities.

LONG–TERM REVERSAL OF TYPE 1 DIABETES IN RATS AFTER IN VIVO DELIVERY OF THE HUMAN INSULIN GENE

O197 Aims: Attempts to replace the β-cells lost in type 1 diabetes include pancreas and islet transplantation, derivation of β-cells from stem cells, and gene therapy. Despite these varied approaches, permanent reversal of type 1 diabetes is yet to be achieved. The aim of this study was to reverse streptozotocin (STZ)-induced diabetes in Wistar rats. Methods: The human proinsulin gene was cloned into a viral vector. Transduction efficiency was assessed by flow cytometry. We introduced the viral vector which expressed the insulin gene into male Wistar rats (250-300 g in body weight) via the portal circulation. Prior to vector delivery, diabetes was induced by the intraperitoneal injection of STZ (75 mg/ kg body weight). Following delivery of the insulin gene or empty vector, rats were monitored for changes in body weight and blood glucose levels. An intravenous glucose tolerance test was performed after a 14 h fast in untreated (n = 3), empty vector-transduced (n = 4) and insulin vector-trransduced (n=6) rats. At various times (0, 2, 5, 10, 15, 30, 60, 120 min) after the infusion of glucose (0.5 g /kg body weight), blood samples were collected from the tail vein and assayed for glucose and insulin. Two months after vector infusion, liver, pancreas, kidney, spleen and lung were harvested. Expression of insulin was determined by RT-PCR and immunohistochemistry. Results: The ideal amount of vector for successful delivery was 4 X 106 transduction units. Rats treated with the insulin-expressing vector, exhibited normalization of blood glucose levels within 48 h and normoglycaemia was maintained for over 11 months. Insulin was expressed only in the liver of insulin-transduced rats. Glucose tolerance tests revealed that insulin-transduced rats showed similar responses to normal rats. In contrast, diabetic rats that received the empty vector remained hyperglycaemic (blood glucose > 24mmol/L) and failed to increase body weight. Conclusions: This study shows that hepatic insulin gene therapy can induce the long-term reversal of diabetes. Importantly, hepatocytes transfected with transgenic insulin are sufficiently responsive to cure STZ–induced diabetes without inducing hypoglycemia.

Vasculogenic Erectile Dysfunction: Newer Therapeutic Strategies

Despite recent advances in therapy, reversal of vasculogenic erectile dysfunction (ED) is rarely possible. A review of vasculogenic ED may further our understanding of the underlying pathophysiology and help develop more effective curative therapy. We reviewed the mechanisms of vasculogenic erectile dysfunction and discuss the therapies currently available or being developed for possible future use. Penile erection is a complex neurovascular phenomenon that may be affected by hypercholesterolemia, atherosclerotic vascular occlusive disease, veno-occlusive dysfunction and cavernosal fibrosis. Animal models of diffuse pelvic atherosclerosis can be maintained by feeding oral cholesterol and injuring the arterial endothelium. Impaired inflow may be addressed by penile revascularization but this strategy is applicable only in select cases. Neovascularization using vascular growth factors has recently been demonstrated to be feasible in animal models. Permanent reversal of impaired cavernosal relaxation requires control of hypercholesterolemia and lifestyle changes, such as smoking cessation. Cavernosal fibrosis may be reversible via some of the same approaches used in treating Peyronie's disease but to date little clinical success has been reported. Venous ligation appears to have a limited role in treating veno-occlusive dysfunction only in highly selected men with minimal cavernosal smooth muscle dysfunction. Hypoxemia, sleep apnea and respiratory failure may also affect erectile dysfunction. However, little attention has been paid to oxygen as therapy for ED. Current therapy, while effective in circumventing vasculogenic ED, is relatively ineffective in permanently reversing the condition. Further research aimed at long-term treatment strategies in vasculogenic ED is needed.

Micro-magnetic and electric analysis on MR head baseline popping and instabilities

A general explanation for four types of instabilities in magneto-resistive (MR) recording heads is given. A micro-magnetic analysis of the root causes of the instabilities shows that baseline popping (BLP), permanent magnet reversal instability (PMRI), spiking noise and writer induced instability have the same root cause as random telegraph noise (RTN) which was reported previously. The details and differences in the formation of each individual phenomenon by the same cause have been investigated in this paper. An MR reader and pre-amplifier electric circuit simulation confirms that baseline popping is due to random telegraph baseline shift passing through a pre-amp DC blocking capacitor which is discharged and recharged at the two levels of the baseline.

Gliomatosis cerebri: intra vitam stereotactic determination in two cases and review of the literature

Gliomatosis cerebri (GC) is an infiltrative neoplastic process that is diffusely distributed through neural structures, whose anatomical configuration remains intact. Most of the cases with GC reported in the literature were diagnosed at autopsy (101/110, 92%). We report two cases of GC in a 42-year-old woman and a 65-year-old man. The diagnosis was confirmed neuropathologically after MRI-guided stereoetactic biopsy. External radiation therapy was performed and led to a complete recovery of all clinical signs. Follow-up examinations 17 and 21 months after diagnosis showed permanent reversal of all clinical and radiological signs. MRI should be used as a primary imaging study in the evaluation of GC and for the determination of the target points for stereotactic biopsy. We discuss the aetiology, clinical manifestation, difficulties of intra vitam diagnosis, and management of this rare condition in the light of other 110 (101 postmortem and nine intra vitam ) reported cases of GC in the literature.

Behavioral Health Benefits In Employer-Sponsored Health Plans, 1997

Data for 1997 show that three-quarters or more of employer-sponsored health plans continue to place greater restrictions on behavioral health coverage than on general medical coverage. The nature of these restrictions varies by plan type. Some improvement in the treatment of mental health/substance abuse (MH/SA) benefits in employer plans may be occurring, however. Comparisons with data from 1996 show that the proportion of plans with benefits for "alternative" types of MH/SA services, such as nonhospital residential care, has increased. Further, the proportion with special limitations on these benefits shows a modest decrease.

Selected applications of capillaries with dynamic or permanent anodal electroosmotic flow in chiral separations by capillary electrophoresis

The techniques for a dynamic and permanent reversal of the electroosmotic flow (EOF) were used for the reversal of the enantiomer migration order (EMO) of neutral and cationic analytes in chiral capillary electrophoresis (CE). Native β-CD and an anionic CD derivative, CM-β-CD were used in both, bare silica- and positively coated capillaries. Advantages and disadvantages of a dynamic and permanent modification of the capillary inner surface are briefly discussed.

Transcranial Doppler Comparison of Balloon Angioplasty and Papaverine Infusion for the Treatment of Intracranial Vasospasm Following Aneurysmal Subarachnoid Hemorrhage

Introduction: We employed daily transcranial Doppler (TCD) evaluation following subarachnoid hemorrhage (SAH) to assess the relative success of balloon angioplasty (BA) and papaverine infusion (PI) with respect to permanent reversal of proximal arterial vasospasm (VSP) associated with delayed ischemic deficits. Methods: In patients treated between 1989 and 1995, TCD blood velocities of the involved distal ICA or proximal MCA were assessed in relation to the day of treatment with BA and or PI. Immediate pre-treatment velocity was compared to the velocity at 24 and 48 hours post-treatment for each vessel using the one-tailed paired-samples T Test. Vessels treated simultaneously with BA and PI were excluded. Vessels treated successively with PI and BA, or with repeated BA or PI, were included in the original treatment cohort until the day of the subsequent treatment. Results: Overall, 211 vessels segments were treated in 83 patients; the present study concerns 102 vessel segments treated...

Reversal of ferroelectric domains by ultrashort optical pulses.

The response of a soft-phonon ferroelectric material subjected to a high-intensity optical pulse of duration much shorter than the period of the phonon is modeled using a classical, finite-temperature simulation. It is found that complete, permanent reversal of the orientation of the ferroelectric domains may occur even when the energy per atom imparted by the light pulse is much less than the average thermal energy. The result raises the possibility of using the effect to create optical switches or data storage media with switching times less than 10 psec.

Sequential treatment with low dose almitrine bismesylate in hypoxaemic chronic obstructive airways disease

Daily dose schedules of 100-200 mg of almitrine bismesylate improve arterial blood gases in patients with hypoxaemic chronic obstructive airways disease (COPD) but dose related side effects are evident. In the present study, daily doses approximately half of those previously used were employed in a randomised double blind manner in 85 patients (age 35-79 years) with hypoxaemic COPD. After a one month period to check stability of arterial blood gases, patients were allocated to almitrine (A) or placebo (P) using an unequal code (60% A, 40% P). Tablets, 50-100 mg daily were stopped for one month after 3, 6 and 9 months to counteract drug accumulation. 50 patients in group A and 35 in group P were comparable on entry; mean age 65 (SD = 8) yrs., Pao2 7.8 (0.7) kPa (58.3 (5.0) mmHg), PaCO2 5.8 (0.8) kPa (43.2 (6.0) mmHg), forced expiratory volume in one second--FEV1 0.89 (0.25) l and 6 minute walking distance 296 (97) metres. The improvement in baseline PaO2 values was the same 0.8-1.3 kPa (6-9.8 mmHg) as with previous higher dose therapy. Approximately one third of patients did not respond, defined as PaO2 elevation > 0.67 kPa (5 mmHg). The sequential dosing scheme stabilised blood levels of almitrine within the therapeutic range of 280-300 ng.ml-1. After withdrawal of therapy arterial blood gases and spirometry reverted to pre-treatment levels, suggesting no permanent reversal of pathophysiology. Dose related side effects of breathlessness, indigestion and peripheral neuropathy were not observed. Nerve conduction studies revealed no difference in peripheral nerve dysfunction in hypoxaemic COPD between active and placebo therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Subclavian steal phenomenon: a correlation between duplex sonographic and angiographic findings.

Correlation of duplex sonography, angiography of the vertebral artery, and the degree of subclavian or innominate stenosis was carried out in ten patients with the subclavian steal phenomenon. Four successive stages of Doppler waveform were identified by duplex sonography. Three angiographic patterns of decreasing severity, permanent reversal, to-and-fro motion and delayed opacification, were found. Permanent reversal angiograms corresponded to complete reversal or late transient Doppler waveforms. To-and-fro motion and delayed opacification angiograms did not necessarily have a corresponding Doppler pattern. The different stages of subclavian steal phenomenon on duplex sonography correlated significantly with the degree of subclavian or innominate stenosis. Stenosis of at least 60% was found to produce abnormal vertebral artery Doppler sonography, except in one patient. Duplex sonography is considered to be a sensitive and convenient method for detecting abnormal vertebral artery haemodynamics and the subclavian steal phenomenon, but some other factors may be important in producing the Doppler waveforms.

Atropine occlusion in the treatment of strabismic amblyopia and its effect upon the non‐amblyopic eye

A total of 189 cases with amblyopia, where atropine sulphate 1% had been used as a method fo unilateral occlusion, were reviewed. The results show that after atropine had been appropriately applied, permanent reversal of amblyopia is rare, and unwanted side-effects are few and of minor nature. Pupil size, light reflex and accommodation of the atropinized eye appear to be unaffected. The angle of squint was unaffected and fixation of the amblyopic eye either remained unchanged or shifted to a more central point.

Pyloric deformation from peptic disease

We have used double-contrast radiographic techniques to clarify what changes in the configuration and movements of the gastroduodenal junction result when peptic lesions involve the distal gastric segment between the proximal (PPL) and the distal pyloric muscle loop (DPL). Among 50 cases of pyloric ulceration diagnosed during a four-year study period, 18 cases fulfilled all study criteria. Ulcers maintained a consistent location with regard to the muscular structures of the pylorus, and by affecting these structures, led to many strange deformations of the gastric outlet including permanent pseudodiverticula and reversal of pyloric angulation. The most common site for peptic lesions in the pyloric segment was the protuberance of the lesser curvature called the pyloric torus; many torus lesions extended into and destroyed the DPL. This led to widening of the gastric outlet and radiographic evidence of increased duodenogastric reflux. Pyloric closure was further impaired in this setting because the mucosa no longer prolapsed into the gastric outlet and did not occlude the pyloric lumen as it normally does. Less common lesions involved the greater curvature and the PPL. In one patient, scarring of the PPL led to an antral web and gastric hyperperistalsis. This was the only patient who required operation for chronic gastric outlet obstruction. One-third of the 18 patients had reflux esophagitis in addition to peptic pyloric disease. In most patients without additional ulcerogenic risk factors, treatment with antisecretory agents led to the healing of ulcer craters. We conclude that the morphologic and functional changes of the gastric outlet caused by peptic lesions depend, in part, on the effect the ulcer has on the underlying pyloric musculature.(ABSTRACT TRUNCATED AT 250 WORDS)

Microvascular exchange and interstitial volume regulation in the rat: implications of the model.

The present work uses and extends a dynamic mathematical model [J. L. Bert, B. D. Bowen, and R. K. Reed. Am. J. Physiol. 254 (Heart Circ. Physiol. 23): H384-H399, 1988] to investigate microvascular exchange and interstitial fluid volume regulation in the rat. Alternative concepts of transcapillary exchange as well as other parametric changes were incorporated into the model. In all cases, predictions resulting from these changes did not describe the available experimental information as well as the original model. A sensitivity analysis of the model showed the microvascular exchange system to be well regulated near its normal steady-state conditions through passive readjustment of the forces participating in the volume regulation. The transient rates of fluid and protein exchange were studied in order to determine the mechanisms inherent in the model that lead to fluid volume regulation during episodes of increased venous pressure and hypoproteinemia. In addition to interstitial compliance, lymph flow characteristics, and washdown of interstitial proteins, it was found that the magnitude and direction of reabsorption played an important role in the regulation process. Edema was always associated with a permanent reversal of the reabsorptive flow.

Lichen aureus: A hemosiderin tattoo associated with perforator vein incompetence

We present evidence that lichen aureus results from extravasation of red blood cells into the dermis caused by incompetence of an underlying perforator vein. The sudden appearance of the lesion suggests a "blow out" of the microvasculature of the lower dermis caused by failure of the valves in the perforator vein. This incompetence of the perforator vein induces a permanent reversal in normal blood flow. The consequent continuous high pressure in the cutaneous microvasculature is responsible for long-term leakage of red blood cells. Digestion of the extravasated red cells by macrophages leaves an "auto-tattoo" of insoluble hemosiderin granules, which produce the distinctive golden or burnt orange color of lichen aureus.

Treatment of Dystonia Musculorum Deformans

To the Editor.— In the QUESTIONS AND ANSWERS section ofThe Journal, 1 an inquiry was made regarding the treatment of dystonia musculorum deformans in a 30-year-old woman who had been suffering from the condition in one foot for 21 years. Although I have no quarrel with the answer as given, I wish to call attention simply to the omission of any reference to neurosurgical treatment. In intractable cases this is often helpful and, at times, almost curative. Patients who do not respond to drug treatment using muscle relaxants and to physical measures such as were properly emphasized in the answer given can often obtain significant and permanent reversal of the distressing symptoms by means of stereotaxic cryothalamectomy on the side opposite to the dystonic limb. The surgical risks are about 1% for both mortality and significant morbidity, and the overall rate of substantial improvement in experienced hands is about

Transplantation of isolated pancreatic islets: current status and prospects.

Complete and permanent reversal of diabetes by transplantation of isolated pancreatic islets has been repeatedly demonstrated experimentally, whereas islet isolation and transplantation in man are associated with largely unsolved problems: the standard isolation procedure including disruption of acini and collagenase digestion is ineffective. Improvement of the islet yield is currently obtained in animal and human trials by using substances selectively acting on exocrine tissue and others protecting the islets at the isolation as well as in tissue culture media. Islet tissue banks and repeated transplantations seem to be realistic also in man. Islets are advantageously implanted intraportally in the liver. They are rejected soon without protection or efficient immunosuppression. Intense research concerns islet-containing diffusion chambers, macrophage suppression, new immunosuppressive agents and induction of immunological tolerance. A successful solution of the technical and immunological problems will aggravate a shortage of donor tissue, already noticeable in the experimental work: this will make the recipient selection crucial.