Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy

The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.     

Biochemical investigation with regard to infection and immunity of Eimeria acervulina in the fowl

Summary Biochemical investigation of the fluid surrounding the sporocysts in the oocysts (oocyst fluid) showed the presence of the common amino acids, -isoaminobutyric acid, glycerol, an unidentified carbohydrate and proteins.Incubation experiments with D-glucose-¹⁴C (U) revealed the presence of enzymes able to convert glucose into lactic acid and other acids. Inside the sporocysts the common amino acids, glycerol and the unidentified carbohydrate were also present, but -isoaminobutyric acid did not occur. The carbohydrate binding protein carboglutelin, carbohydrate phosphate and small amounts of glucose and fructose were mainly found inside the sporocysts.Incubation experiments of oocyst fluid mixed with sporocysts with D-glucose-C¹⁴ (U) demonstrated an interchange between the fluid and the sporocysts. In the oocyst fluid lactic acid was formed, but inside the sporocysts the conversion appeared to stop mainly with formation of carbohydrate phosphate.Incubation experiments of intestinal pieces both from immunized and not-immunized birds with oocyst fluid, sporocysts and labelled glucose showed that a stronger reaction took place in immunized birds than in not-immunized ones.Similar experiments were performed with not-immunized birds at different days after a primary infection. The reaction of the intestinal wall, which seemed quite normal again since day 19 after infection, was comparable with that observed in immunized birds.Finally the hypothesis is given, that in the first part of the intestine of immunized birds compounds are present originating from the first infection. These compounds might enhance the reaction between the oocyst fluid and the present feed to such an extent that the pH decreases and much epithelial cells are pushed off possibly together with the sporocysts. Then leakage of serum proteins might occur.     

Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society     

Tackling the scaling-up problem of digital health applications

Journal of Public Health - The purpose of this editorial is to provide guidance for the readers concerning the broad realm of approaches towards successful implementation of digital health...     

Interventions to Increase Multivitamin Use Among Women in the Interconception Period: An IMPLICIT Network Study

Maternal and Child Health Journal - Each year, 3% of infants in the Unites States (US) are born with congenital anomalies, including 3000 with neural tube defects. Multivitamins (MVIs) including...     

Experimental SARS-CoV-2 Infection of Bank Voles

After experimental inoculation, severe acute respiratory syndrome coronavirus 2 infection was confirmed in bank voles by seroconversion within 8 days and detection of viral RNA in nasal tissue for up to 21 days. However, transmission to contact animals was not detected. Thus, bank voles are unlikely to establish effective transmission cycles in nature.     

Looking into the black box of “Medical Innovation”: rising health expenditures by illness type

There is agreement among health economists that on the whole medical innovation causes health care expenditures (HCE) to rise. This paper analyzes for which diagnoses HCE per patient have grown significantly faster than average HCE. We distinguish decedents (patients in their last 4 years of life) from survivors and use a unique dataset comprising detailed HCE of all members of a regional health insurance fund in Upper Austria for the period 2005–2018. Our results indicate that among decedents in particular, the expenditures for treatment of neoplasms have exceeded the general trend in HCE. This confirms that medical innovation for this group of diseases has been particularly strong over the last 15 years. For survivors, we find a noticeable growth in cases and cost per case for pregnancies and childbirth, and also for treatment of mental and behavioral disorders. We discuss whether these findings contradict the widespread interpretation of cost-increasing innovations as “medical progress” and offer some policy recommendations.

     

Differences in the outcomes of scrotal vs. lateral vs. medial inguinal hernias: a multivariable analysis of registry data

Hernia - There are hardly any studies on the outcome of scrotal compared with medial and lateral inguinal hernias. Therefore, this present multivariable analysis of data from the Herniamed Registry...     

Four Additional Questions for the Preparation Hypothesis

Archives of Sexual Behavior -