[Desmopressin in the Treatment of Enuresis: Is Lyophilisate Superior to Tablets?] / Desmopressin in der Behandlung der Enuresis: Ist das Lyophilisat den Tabletten überlegen?

Background: Prognosis of MNE is good when adequate treatment starts in a timely manner. First-line treatment for monosymptomatic nocturnal enuresis (MNE) includes desmopressin (Grade A/Level 1 recommendation from the ICI). Missing or insufficient response to pharmacological treatment can be caused by incomplete compliance, but might also be associated with differences in bioavailability from the tablet form. This prospective, non-interventional study was designed to compare desmopressin tablets to the newer ,,melt'' formulation, also known as lyophilisate or orally disintegrating tablet (ODT). The primary endpoint of this study was the patients'/parents' acceptance; the secondary end point was a decrease in the number of wet nights. Materials and Methods: Each of the scheduled 100 participating doctors had to recruit two MNE candidates, one for each treatment group, with a planned total of 200 participants. At the end of the treatment period, treatment satisfaction, difficulties in taking the medication, forgotten doses and treatment success were reported. Results: In total, 134 patients were included (49 on tablet and 84 on melt). Difficulties in taking the medication and forgotten doses were significantly less with the melt than with the tablet formulation. Treatment satisfaction was better with melt. After the 3 months study, the number of wet nights was considerably reduced in both groups. With lyophilisate, a statistically significant greater reduction in wet nights was recorded as early as 2 weeks after starting the treatment. Conclusion: Desmopressin as orally disintegrating tablets is an effective treatment and is associated with improved patient compliance.

Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. a pilot study.

Retinopathy is the most common microvascular diabetes complication and represents a major threat to the eyesight. The aim of this study was to address the role of pro- and anti-angiogenic molecules in diabetic retinopathy in the aqueous humor of the eye. Aqueous humor was collected at cataract surgery from 19 diabetic patients and from 13 age- and sex-matched normoglycemic controls. Levels of pro-angiogenic vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) were determined. Angiogenic activity of the aqueous humor was quantified by measuring its effect on the migration of capillary endothelial cells. In the aqueous fluid, VEGF levels were increased in diabetics (mean values: 501 vs. 367 pg/ml; p = 0.05), compared to controls. PEDF was found to be decreased in diabetics (mean values: 2080 vs. 5780 ng/ml; p = 0.04) compared to controls. In seven diabetic patients with proliferative retinopathy, the most profound finding was a significant decrease of the PEDF level (mean value: 237 ng/ml), whereas VEGF levels were comparable to diabetic patients without proliferation (mean value: 3153; p = 0.003). Angiogenic activity in samples of patients from the control group was generally inhibitory due to PEDF, and inhibition was blocked by neutralizing antibodies to PEDF. Likewise, in diabetics without proliferation, angiogenic activity was also blocked by antibodies to PEDF. We will demonstrate here that the level of the natural ocular anti-angiogenic agent PEDF is inversely associated with proliferative retinopathy. PEDF is an important negative regulator of angiogenic activity of aqueous humor. Our data may have implications for the development of novel regimens for diabetic retinopathy.

Efficacy and safety of memantine, an NMDA-type open-channel blocker, for reduction of retinal injury associated with experimental glaucoma in rat and monkey.

Glutamatergic excitotoxicity has been implicated as a mechanism for injury in a variety of central nervous system pathologies, including glaucoma. Memantine, an NMDA-type glutamatergic open-channel blocker, has pharmacologic properties that make its efficacy greater under excitotoxic conditions, but lesser under normal conditions. Daily oral dosing for approximately 15 months with 4.0 mg/kg memantine in monkeys yielded plasma concentrations similar to those found in patients who received memantine treatment for Parkinson's disease. This same dose of memantine was not associated with any evidence of an effect on the normal function of the retina and central visual pathways, as indicated by measures of the electroretinogram (ERG) and visually-evoked cortical potential (VECP). Amplitude of the VECP response was reduced in eyes with experimentally induced glaucoma. When compared to vehicle-treated control animals, memantine-treated glaucoma eyes suffered significantly less reduction of VECP amplitude. Preliminary results in a rat model for experimental glaucoma also show that, when compared to control animals, systemic treatment with memantine (10 mg/kg/day) was associated with a significant reduction in glaucoma-induced loss of retinal ganglion cells.

Characterization of retinal injury using ERG measures obtained with both conventional and multifocal methods in chronic ocular hypertensive primates.

PURPOSE: To characterize, using both conventional and multifocal electroretinogram (ERG) recordings as well as histologic measures, retinal injury in the chronic ocular hypertensive primate model for experimental glaucoma. METHODS: Ocular hypertension was induced in the right eye of 7 cynomolgous monkeys, Macaca fascicularis, using laser injury to the aqueous outflow tissue at the anterior chamber angle. At 16 months after IOP elevation, ERG recordings were made from both eyes of all animals using both conventional and multifocal methods. After electrophysiological recording, animals were killed and retinal samples were radially sectioned for histologic analysis. RESULTS: Histologic measures showed that ocular hypertensive injury was largely or completely limited to a loss of retinal ganglion cells (RGCs). The degree of RGC loss was similar in central and peripheral retina. Amplitudes of conventional ERG responses were mostly unaffected in eyes having severe loss of RGCs, a finding that is consistent with limited injury to photoreceptors, bipolar cells, and amacrine cells. Peaks in both the first- and second-order multifocal ERG responses were attenuated in ocular hypertensive eyes, and amplitude of these peaks was highly correlated with the density of surviving RGCs. CONCLUSIONS: The results are consistent with a conclusion that both first- and second-order components of the multifocal ERG response from the monkey reflect a significant contribution from activity in RGCs and may provide a useful measure for the clinical diagnosis and management of glaucoma.

Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region.

Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single-strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5' region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.

Thoughts on the condolence letter.

Genuine, specific, timely emotional support of caregivers at the time of euthanasia is an important part of the veterinary professional obligation. Such support helps ease client pain during the grieving process. However, caution and sensitivity are essential when assessing and responding to caregiver-companion animal relationships.(1) For example, some caregivers are highly bonded but conceal their emotions, so our perceptions and responses must be thoughtful and discerning. My veterinary technician and I are supportive of our clients during euthanasia. I later write the condolence letter according to our perceptions of that particular human-companion animal bond. The only exceptions to our attempt to be thoroughly supportive at the time of euthanasia are those instances when we perceive that there has been obvious and willful abuse or neglect. At such times, we try to maintain emotional neutrality. The condolence letter and its variations described here are intended to serve as a guide. We send the condolence letter to caregivers within 24 hours of euthanasia, and it is addressed to the entire family. In addition, a euthanasia packet is provided at the time of euthanasia. The packet includes 2 brochures on coping with the loss of a companion animal, (2,3) contact information for a pet loss support hotline and a pet loss support group, an essay and a poem about the death of a companion animal, and a how-to article on dealing with children and their emotions on the loss of a pet. (4) My veterinary technician almost always phones the caregiver 1 to 3 days after euthanasia of their companion animal. The timing of the call depends on the circumstances of death and our judgment as to the emotional needs of the caregiver and family. Where emotions around euthanasia and loss are especially deep, the follow-up call may be made as early as that night or the next morning, with a second call 2 to 3 days later. The nature of the conversation depends on the technician's perception of the caregiver's needs. A condolence letter should reflect the needs and values of the individual veterinarian. For example, McElyea includes a brief history or profile of the animal and a reminder that death was easy and without suffering. (5) Others may wish to send a separate condolence to a child who seems especially affected by the death and loss of their special friend. I hope this article will encourage colleagues to hand-write condolence letters that reflect positive personal thoughts and feelings about the patient, the client, and the circumstances of the loss.

Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma.

Vascular endothelial growth factor (VEGF), a multifunctional cytokine, potently stimulates angiogenesis including tumor neovascularization. Although well established in solid tumors, the role of VEGF in bone marrow neoangiogenesis and paracrine tumor-stromal cell interactions in lymphohematopoietic malignancies has not been fully elucidated. In multiple myeloma (MM), marrow neovascularization parallels disease progression. This parallel prompted us to investigate the expression and secretion of VEGF by myeloma cells and its potential effects in myeloma-marrow stroma interactions. The biologically active splice variants VEGF165 and VEGF121 were expressed and secreted by myeloma cell lines and plasma cells isolated from the marrow of patients with MM. As shown by immunocytochemistry or RT-PCR, myeloma cells did not express or weakly expressed the VEGF receptors FLT-1 and FLK-1/KDR, indicating that autocrine stimulation is unlikely. In contrast, FLK-1/KDR was abundantly expressed by marrow stromal cells. Therefore, we studied the effects of VEGF on marrow stroma, focusing on the secretion of interleukin-6 (IL-6), a potent growth factor for myeloma cells and an inhibitor of plasma cell apoptosis. Exposure of stromal and microvascular endothelial cells to recombinant human (rh) VEGF165 or VEGF121 induced a time- and dose-dependent increase in IL-6 secretion (14- to 27-fold at 50 ng/mL after 24 hours, P <.001). Conversely, rhIL-6 stimulated VEGF expression and secretion in myeloma cell lines (40%-60%; P <.05) and to a variable degree (up to 5.3-fold; P <.005) in plasma cells purified from the marrow of patients with MM. This mutual stimulation suggests paracrine interactions between myeloma and marrow stromal cells triggered by VEGF and IL-6. (Blood. 2000;95:2630-2636)

Diabetic retinopathy is associated with decreased serum levels of free IGF-I and changes of IGF-binding proteins.

In patients with diabetic retinopathy, elevated serum levels of total circulating insulin-like growth factor-I (IGF-I) have been implicated as an important mediator of the disease. There is no study, however, measuring free IGF-I levels in patients with diabetic retinopathy which mediate the biological effects of IGF-I and are modulated by a complex system of six specific IGF binding proteins (IGFBPs) and several IGFBP proteases.

[Decreased serum level of free bioavailable IGF-I in patients with diabetic retinopathy]. / Verminderte Serumspiegel von freiem bioverfügbarem IGF-I bei Patienten mit diabetischer Retinopathie.

BACKGROUND: Growth factors like IGF-I have been implicated in the pathogenesis of diabetic retinopathy. To investigate the role and bioavailability of IGF-I we measured not only total but also free serum levels of IGF-I in diabetic patients. METHODS: A total of 159 patients with and without diabetic retinopathy were investigated (60 diabetic patients without and 99 with clinically and angiographically diagnosed diabetic retinopathy). One hundred ten healthy volunteers served as controls. The data were analyzed by Student's t-test, analysis of variance and correlation; P < 0.05 was considered statistically significant. RESULTS: Diabetic patients with retinopathy showed significantly lower serum levels of free IGF-I than diabetics without retinopathy. Free IGF-I was negatively correlated with glycosylated hemoglobin 1c. IGFBP-3 levels were diminished in type 2 patients with diabetic retinopathy, while type 1 patients with diabetic retinopathy showed higher IGFBP-1 levels. CONCLUSION: Diabetic patients with retinopathy showed significantly reduced serum levels of free IGF-I. Low IGF-I was associated with poor metabolic control.

Electrophysiological and histological measures of retinal injury in chronic ocular hypertensive monkeys.

PURPOSE: This study was performed to determine whether components of the standard ERG (electroretinogram), multifocal ERG, and flash VECP (visually-evoked cortical potential) response might provide a sensitive measure of retinal ganglion cell injury in a monkey model for chronic ocular hypertension. METHODS: Argon laser treatment of the aqueous outflow tissue was used to induce chronic elevation of intraocular pressure (IOP) in the right eye of 18 young adult cynomolgous monkeys. At 15 months post- IOP elevation, standard methods were used to record ERG and VECP responses. Multifocal ERG responses were also recorded at this time. Loss of retinal ganglion cells due to ocular hypertensive injury was determined by histological analysis of all retinas. RESULTS: Ocular hypertensive retinal injury was associated with a loss of retinal ganglion cells. There was no histological or electrophysiological evidence for injury to any other retinal cell type. Correlation of electrophysiological response amplitudes with histological measures of retinal ganglion cell loss/survival yielded results which suggest that activity in retinal ganglion cells makes a substantial contribution to components of the 30 Hz flicker ERG, the flash VECP, and both first and second order multifocal ERG responses. Of the electrophysiological measures used in this study, multifocal ERG response amplitude had the greatest sensitivity to retinal ganglion cell loss. CONCLUSIONS: Components of the multifocal ERG provide a sensitive measure of ganglion cell injury in a monkey model of chronic ocular hypertension. These same measures may have utility in the clinical diagnosis and management of glaucoma.

Characterization of muscarinic receptors in cultured human iris sphincter and ciliary smooth muscle cells.

Muscarinic receptors present in cultured human iris sphincter and ciliary smooth muscle cells were characterized by both ligand ([3H]QNB binding) and functional (phosphoinositide hydrolysis) studies. Ligand binding studies showed that [3H]QNB represented a single population of binding sites with KD values of 4.02 x 10(-11) M in the ciliary and 5.6 x 10(-11) M in the iris sphincter cells. In competition studies, the selective antagonist, 4-diphenylacetoxy-N-methylpiperidine-methobromide (4-DAMP) was the most potent in displacing [3H]QNB with selectivity of 150-350-fold over pirenzepine (M1) and 450-1700-fold over AF-DX 116 (M2). 4-DAMP recognized one site in the iris sphincter cells (Ki = 0.34 nM) but two sites in the ciliary cells (KH = 0.9 nM and KL = 49 nM). 4-DAMP was also the most potent in inhibiting carbachol-induced hydrolysis of inositol phospholipids (PI) in both cell types. However, the IC50 values for PI hydrolysis were several fold lower than those for [3H]QNB binding. Using these selective antagonists, our data supports the presence of functional muscarinic receptors of M3 subtype in human iris sphincter and ciliary cells. It also shows the presence of a second low affinity site in the ciliary smooth muscle cells that is recognized by 4-DAMP.

[Aluminum poisoning caused by the phosphate binder in a non-dialysed child with chronic renal insufficiency]. / Aluminiumintoxikation durch Phosphatbinder bei einem nicht dialysierten Kind mit chronischer Niereninsuffizienz.

In patients with chronic renal failure, aluminium, which is included in the dialysate or released from phosphate binders, cannot be eliminated adequately. It forms a deposit in the tissues and leads to intoxication. After a 6-month therapy with aluminium-containing phosphate binders in a non-dialysed baby with chronic renal insufficiency, an osteomalacia arose with distinct subepiphyseal and metaphyseal changes attributable to disorders of mineralization. The consequence of this was a "bone-within-bone" appearance and pathological fractures. After a change of therapy, the bone alterations receded within a few months. Simultaneously, the distinctly elevated serum level of aluminium fell. Therefore, aluminium should be avoided in non-dialysed children with chronic renal insufficiency.