Offering HCV treatment to prisoners is an important opportunity: key principles based on policy and practice assessment in Europe.

BACKGROUND: Prisoners have a high prevalence of hepatitis C virus (HCV) infection but may find it difficult to access healthcare services. This may be related to risk behaviour including history of injecting drugs and marginalisation related to problem drug use/ opioid use disorder (OUD). Direct-acting antiviral products with superior efficacy and safety compared to interferon-based regimens offer HCV cure. Many citizens in Europe have been treated, although few received therapy in prisons. METHODS: Analysis of prisoner HCV treatment need and policy determinants of clinical practice was completed for 5 EU countries. Evidence was collected from national statistical sources and peer-reviewed publications to describe prison populations and HCV prevalence, to map national prison/ HCV health policy or guidance. A consensus of important principles for prisoner HCV care was developed. RESULTS: Data from published sources describing prisoner HCV prevalence is limited. Prisoner population requiring HCV treatment is not known; estimated numbers based on analysis of evidence: England and Wales, 9000, France, 8000, Spain, 6000, Italy, 6000, Germany, 6000. Treatment access: national law defines right to equivalent care in all countries implying access to HCV therapy in prison similar to community; useful prisoner HCV guidance facilitating treatment decisions present in: 4 of 5 national/ regional HCV policy documents, 4 of 5 national prison healthcare policies. Four of five had practical prison HCV clinical guidelines. Despite existence of policy, implementation of guidance, and so HCV treatment, is suboptimal in many locations. CONCLUSIONS: Prison is an important location to detect, address and treat HCV infection in people who may be underserved for healthcare and find it difficult to navigate community treatment pathways. This is often related to problems with OUD and resulting social inequity. HCV management in prisons must be improved. Policy and clinical practice guidance must be set to promote treatment, and practical steps to make treatment easy should be followed including education to promote engagement, set-up of optimal screening and work up processes with modern tools to reduce time needed/ achieve efficiency; programs to make it easier to get specialists' input include remote working and nurse-led services.

Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing.

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.

Comparison of environmental risk factors for esophageal atresia, anorectal malformations, and the combined phenotype in 263 German families.

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and anorectal malformations (ARM) represent the severe ends of the fore- and hindgut malformation spectra. Previous research suggests that environmental factors are implicated in their etiology. These risk factors might indicate the influence of specific etiological mechanisms on distinct developmental processes (e.g. fore- vs. hindgut malformation). The present study compared environmental factors in patients with isolated EA/TEF, isolated ARM, and the combined phenotype during the periconceptional period and the first trimester of pregnancy in order to investigate the hypothesis that fore- and hindgut malformations involve differing environmental factors. Patients with isolated EA/TEF (n = 98), isolated ARM (n = 123), and the combined phenotype (n = 42) were included. Families were recruited within the context of two German multicenter studies of the genetic and environmental causes of EA/TEF (great consortium) and ARM (CURE-Net). Exposures of interest were ascertained using an epidemiological questionnaire. Chi-square, Fisher's exact, and Mann-Whitney U-tests were used to assess differences between the three phenotypes. Newborns with isolated EA/TEF and the combined phenotype had significantly lower birth weights than newborns with isolated ARM (P = 0.001 and P < 0.0001, respectively). Mothers of isolated EA/TEF consumed more alcohol periconceptional (80%) than mothers of isolated ARM or the combined phenotype (each 67%). Parental smoking (P = 0.003) and artificial reproductive techniques (P = 0.03) were associated with isolated ARM. Unexpectedly, maternal periconceptional multivitamin supplementation was most frequent among patients with the most severe form of disorder, i.e. the combined phenotype (19%). Significant differences in birth weight were apparent between the three phenotype groups. This might be attributable to the limited ability of EA/TEF fetuses to swallow amniotic fluid, thus depriving them of its nutritive properties. Furthermore, the present data suggest that fore- and hindgut malformations involve differing environmental factors. Maternal periconceptional multivitamin supplementation was highest among patients with the combined phenotype. This latter finding is contrary to expectation, and warrants further analysis in large prospective epidemiological studies.

[Prison health is public health! Problems in adapting and implementing health services for prisoners in Germany. A review]. / Prison Health is Public Health! Angleichungs- und Umsetzungsprobleme in der gesundheitlichen Versorgung Gefangener im deutschen Justizvollzug Ein Ubersichtsbeitrag.

On the basis of international standards, health care in German prisons has been oriented along the principle of equivalence (equity of health care delivery for inmates compared with the health care delivery in the community). Against this background, selected health problems demonstrate not only isolated problems in adaptation and implementation of health care delivery, but also structural problems resulting from the parallel system of prison health care, which is separated from the general German health care insurance system. This review serves as a basis to present suggestions to rethink and reorganize prison-based health care services.

[On line ophthalmologic education. Live transfers and on demand lectures via Internet]. / Augenärztliche Online-Fortbildung. Live-Ubertragungen und On-demand-Vorträge via Internet.

Continuing medical education for ophthalmologist is important and demanded from the board of ophthalmic organizations. The use of new multimedia possibilities provided by the internet, offers an alternative to acquire the training sessions requested by the board. Aim of the paper is to show the efforts made, to place an internet-based training website for ophthalmologists by transferring live ophthalmology events via the internet. The live-transfers of selected lectures is realized by transferring the original sound compatible to the software "Real-Audio-Player" with an rate of 8000 Hz (encoding-depth 14 bits). By using this software it is possible to follow the lectures live. It includes also 2 live-pictures of 2 digital camcorders to show the appropriate slides from the lecturer. The live broadcasted lectures were afterwards revised and are available at any time as "on-demand lectures" with original sound and slides. Since November 1997, 15 continuing medical education events for ophthalmologists of the University Erlangen-Nürnberg, Germany and from other universities were live broadcasted covering all aspects of phthalmology can be viewed as "on-demand lectures" with original-sound and slides under the internet-addresse http:¿www.onjoph.com/deutsch/live.html. The broadcasted events of workshops were watched via the internet with the appropriate software by 3500 persons, and approximately 5200 persons were listening at least one of the lectures since 1997.

[Transmission of infectious diseases during imprisonment--results of a study and introduction of a model project for infection prevention in Lower Saxony]. / Ubertragungen von Infektionskrankheiten im Justizvollzug--Ergebnisse einer Untersuchung und Vorstellung eines Modellprojektes zur Infektionsprophylaxe in Niedersachsen.

The increasing imprisonment rate of drug users is linked to a spread of infectious diseases in prisons (HIV and Hepatitis B and C). Several studies indicate a close correlation of imprisonment and transmission of infectious diseases. An analysis of international studies showed that worldwide in several cases transmissions of HIV-infection during imprisonment have been discovered. The cross-sectional examination presented here is describing the situation in the women's prison of Vechta (Lower-Saxony). Empirical data on the prevalence of infections with HIV, HBV, HCV and Lues of the years 1992 to 1994 were recorded. Moreover the scientific interest also included on the diagnosis of seroconversions. Discovered seroconversions were examinated on a possible transmission in custody. The spread of infectious diseases in prisons led to the demand for an alignment of internal drug aid services with external, tried and tested prophylaxis models. The availability of sterile syringes is included. The basic comparability of health care inside and outside prison (principle of equivalence) is not only demanded and recommended by the prison law [4] but also by international organisations [27]. As the first provencial government, the state of Lower Saxony in Germany has started to develop infection prophylaxis offers in two prisons (in the women's prison in Vechta since April 15th 1996 and in the men's prison of Lingen I, department Gross Hesepe since July 15th 1996) in 1996. These offers include the provision of sterile injection equipment to intravenous drug addicts (ivDA). Modalities of the practice and first experiences documented by the schientific evaluation are presented.

Use of bacteriocinogenic lactic acid bacteria to inhibit spontaneous nisin-resistant mutants of Listeria monocytogenes Scott A.

Nisin is a bacteriocin with a broad antibacterial spectrum including strains of Listeria monocytogenes. Populations of L. monocytogenes, however, frequently contain spontaneous nisin-resistant mutants. When a culture of L. monocytogenes Scott A was exposed to nisin concentrations between 10 and 500 IU ml-1, the initial decrease in viable numbers was followed by regrowth of survivors to nisin. Nisin-resistant mutants of L. monocytogenes Scott A were isolated after a single exposure to nisin at 100 IU ml-1 and were shown to be sensitive to the non-nisin bacteriocins, sakacin A and enterocin B, produced by Lactobacillus sake Lb 706 and Enterococcus faecium BFE 900, respectively. The regrowth of L. monocytogenes Scott A following the initial decrease due to exposure to nisin was prevented by nisin-resistant Lact. sake Lb 706-la and to a somewhat lesser extent, by Ent. faecium BFE 900-6a. Listerial cells surviving nisin action were thus inhibited by the bacteriocin-producing strains that might be used as starter or protective cultures in foods. Growth of a nisin-resistant mutant of L. monocytogenes Scott A (Li3) was also suppressed by the bacteriocinogenic cultures. Use of nisin in combination with a starter culture producing a non-nisin antilisterial bacteriocin may therefore prevent the emergence of nisin-resistant mutants of L. monocytogenes.

Clinical phase I and pharmacokinetic trial of the new titanium complex budotitane.

Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established screening models indicate considerable antitumor activity. We have performed a clinical Phase I and pharmacokinetic trial with budotitane administered as i.v. infusion twice weekly. The starting dose of 100 mg/m2 was derived from a prior single dose Phase I study. Eighteen patients with solid tumors refractory to all other known treatment modalities were entered. 17 patients had received prior chemotherapy. Dose levels ranged from 100 mg/m2 to 230 mg/m2, with a total of 122 budotitane infusions administered. Neither leuko- nor thrombocytopenia were observed. 2/5 pts at 180 mg/m2 and 2/4 pts at 230 mg/m2 developed a 3-fold increase of reticulocytes without signs of hemolysis or bleeding. Nonhematologic toxicity was moderate at doses of < or = 180 mg/m2. Fifteen patients reported loss of taste at the day of infusion. At 230 mg/m2, 2/4 pts developed WHO grade 3 cardiac arrhythmias with polytope premature ventricular beats and nonsustained ventricular tachycardia. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m2 and 230 mg/m2. At 180 mg/m2, Cmax was 2.9 +/- 1.2 microg/ml, t1/2 78.7 +/- 24.4 h, Cltot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h x microg/ml. At 230 mg/m2, Cmax was 2.2 +/- 0.8 microg/ml, t1/2 59.3 +/- 12.1 h, Cltot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h x microg/ml. No objective tumor response was observed. We conclude that the maximum tolerated dose of budotitane administered twice weekly is 230 mg/m2, the dose limiting toxicity is cardiac arrhythmia. Further evaluation of the nature of the cardiac toxicities observed is warranted. Using this schedule, 180 mg/m2 is a safe dose for subsequent clinical studies.

Cyanine-related compounds: a novel class of potent inhibitors of extraneuronal noradrenaline transport.

The neurotransmitter noradrenaline is removed from the extracellular space by neuronal and extraneuronal transport mechanisms. In the past, further functional and biochemical characterisation of the corticosterone-sensitive extraneuronal transporter was hampered by the lack of highly potent inhibitors. Here we describe a new class of selective and highly potent inhibitors of the extraneuronal noradrenaline transporter. Clonal Caki-1 cells possess the human type of extraneuronal noradrenaline carrier. The effect of various steroids and steroid-like compounds on initial rates of specific 3H-noradrenaline transport in Caki-1 cells was investigated. None of these steroids had an inhibitory potency higher than that of corticosterone which hitherto was generally accepted as the most potent inhibitor of the extraneuronal noradrenaline transport. On the other hand, a variety of quinoline and isoquinoline derivatives interacted with the extraneuronal noradrenaline transporter. Several cationic quinolines that belong to the chemical class of the cyanine dyes turned out to be very potent inhibitors of 3H-noradrenaline transport in Caki-1 cells. The isocyanines, 1,1'-diisopropyl-2,4'-cyanine (disprocynium24) and 1-methyl-1'-isopropyl-2,4'-cyanine as well as the pseudoisocyanines 1,1'-diethyl-2,2'-cyanine (decynium22) and 1-isopropyl-1'-ethyl-2,2'-cyanine (iprecynium22) were most potent with IC50's of 14, 62, 16, and 18 nmol/l, respectively. The inhibitory potency on extraneuronal noradrenaline transport of 1-methyl-1'-isopropyl-2,4'-cyanine was determined also in isolated organs, namely the isolated incubated rabbit aorta and the isolated perfused rat heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Variable presentation of cytochrome c oxidase deficiency.

OBJECTIVE: To describe three patients with cytochrome c oxidase deficiency. DESIGN: Patient series. SETTING: Tertiary care children's hospital in Arkansas. PARTICIPANTS: A sibling pair and an unrelated patient referred for evaluation and found to have cytochrome c oxidase deficiency. INTERVENTIONS: None. MEASUREMENTS/MAIN RESULTS: Affected individuals had the characteristic presentation of psychomotor regression, growth deficiency, and lactic acidosis. The severity of the clinical course was found to correlate with the lactate-pyruvate ratio. Two of the infants had evidence, on magnetic resonance imaging, of subacute necrotizing encephalomyelopathy (Leigh disease). The most severely affected child had an unusual presentation of prenatal onset of structural anomalies including glabellar prominence, abnormal hair, loose skin, inguinal hernias, and hypospadias. CONCLUSIONS: The presentation and clinical course of cytochrome c oxidase deficiency are highly variable and the diagnosis of cytochrome c oxidase deficiency should be considered in all patients with lactic acidosis or subacute necrotizing encephalomyelopathy. Particular consideration should be given to this diagnosis when lactic acidosis is found in a neonate with structural anomalies.