Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis.

There is considerable genetic and phenotypic heterogeneity associated with intellectual disability (ID), specific learning disabilities, attention-deficit hyperactivity disorder, autism and epilepsy. The intelligence quotient (IQ) motif and SEC7 domain containing protein 2 gene (IQSEC2) is located on the X-chromosome and harbors mutations that contribute to non-syndromic ID with and without early-onset seizure phenotypes in both sexes. Although IQ and Sec7 domain mutations lead to partial loss of IQSEC2 enzymatic activity, the in vivo pathogenesis resulting from these mutations is not known. Here we reveal that IQSEC2 has a key role in dendritic spine morphology. Partial loss-of-function mutations were modeled using a lentiviral short hairpin RNA (shRNA) approach, which achieved a 57% knockdown of Iqsec2 expression in primary hippocampal cell cultures from mice. Investigating gross morphological parameters after 8 days of in vitro culture (8DIV) identified a 32% reduction in primary axon length, in contrast to a 27% and 31% increase in the number and complexity of dendrites protruding from the cell body, respectively. This increase in dendritic complexity and spread was carried through dendritic spine development, with a 34% increase in the number of protrusions per dendritic segment compared with controls at 15DIV. Although the number of dendritic spines had normalized by 21DIV, a reduction was noted in the number of immature spines. In contrast, when modeling increased dosage, overexpression of wild-type IQSEC2 led to neurons with shorter axons that were more compact and displayed simpler dendritic branching. Disturbances to dendritic morphology due to knockdown of Iqsec2 were recapitulated in neurons from Iqsec2 knockout mice generated in our laboratory using CRISPR/Cas9 technology. These observations provide evidence of dosage sensitivity for IQSEC2, which normally escapes X-inactivation in females, and links these disturbances in expression to alterations in the morphology of developing neurons.

Clinical implications of hepatogenous diabetes in liver cirrhosis.

BACKGROUND: Hepatogenous diabetes is a common complication of liver cirrhosis. The aim of the present study was to examine the clinical and therapeutic implications and the prognostic significance of hepatogenous diabetes in patients with liver cirrhosis. METHODS: The prospective cohort study was conducted in 52 patients with histologically confirmed liver cirrhosis (44% Child A, 37% Child B, 19% Child C). The examination included a history, determination of basal C-peptide and glycosylated hemoglobin (HbA(1c)) and, in some cases, a 3 h oral glucose tolerance test with 100 g glucose. Patients were also examined for signs of diabetic retinopathy and information on the further course of illness was obtained. RESULTS: Seventy-one percent of patients with liver cirrhosis had manifest diabetes, 25% had impaired glucose tolerance and only 4% had normal glucose tolerance. In most cases, the hepatogenous diabetes was clinically asymptomatic. Sixteen percent of patients with hepatogenous diabetes had a family history of diabetes; only 8% had retinopathic complications. Within 5.6 +/- 4.5 years after diagnosis of liver cirrhosis, 52% of the diabetics had died, mainly of complications of the cirrhosis. There were no diabetes-associated or cardiovascular deaths. CONCLUSIONS: Hepatogenous diabetes differs from type 2 diabetes in that there is less often a positive family history and that the cardiovascular and retinopathic risk is low. The prognosis of cirrhotic patients with diabetes is more likely to be negatively affected by the underlying hepatic disease and its complications than by the diabetes. Antihyperglycemic treatment of hepatogenous diabetes should always be carefully weighed up in each individual case.

Contra-indications to metformin therapy are largely disregarded.

AIMS: To investigate the current metformin treatment practice and in particular to examine the consideration given to its contraindications. METHODS: A cross-sectional analysis of 308 consecutive Type 2 diabetic patients (mean age 66+/-11.3 years) previously treated with metformin on an outpatient basis and admitted to a German general hospital during the period from 1 January 1995 to 31 May 1998 because of acute disease or in order to optimize their diabetes management. All patients underwent a basic investigation comprising a documentation of their medical history, a physical examination, an electrocardiogram, and an extensive laboratory profile; 34% also had acute coronary angiography. RESULTS: On admission to hospital, 73% of the patients were found to have contra-indications, risk factors, or intercurrent illnesses necessitating discontinuation of metformin; 51% of these patients had several of these conditions. As major contra-indications to metformin, renal impairment was present in 19% of all patients, heart failure in 25%, respiratory insufficiency in 6.5%, and hepatic impairment in 1.3%. The risk factors to metformin included advanced coronary heart disease in 51%, atrial fibrillation in 9.8%, chronic alcohol abuse in 3.3%, advanced peripheral vascular disease in 2%, and pregnancy in 0.7%. As intercurrent illnesses, cerebral ischaemia occurred in 9.8% under metformin treatment and malignancies were diagnosed in 6.5%. The patients with contra-indications or requiring caution to metformin were significantly older and had previously been treated with more cardiovascular medication than those without such reservations (P<0.001). CONCLUSIONS: Despite the considerable risk of lactic acidosis in the majority of patients, no cases were observed.

When doctors marry doctors: a survey exploring the professional and family lives of young physicians.

BACKGROUND: Soon, half of all physicians may be married to other physicians (that is, in dual-doctor families). Little is known about how marriage to another physician affects physicians themselves. OBJECTIVE: To learn how physicians in dual-doctor families differ from other physicians in their professional and family lives and in their perceptions of career and family. DESIGN: Cross-sectional survey. SETTING: Two medical schools in Ohio. PARTICIPANTS: A random sample of physicians from the classes of 1980 to 1990. MEASUREMENTS: Responses to a questionnaire on hours worked, income, number of children, child-rearing arrangements, and perceptions about work and family. RESULTS: Of 2000 eligible physicians, 1208 responded (752 men and 456 women). Twenty-two percent of male physicians and 44% of female physicians were married to physicians (P < 0.001). Men and women in dual-doctor families differed (P < 0.001) from other married physicians in key aspects of their professional and family lives: They earned less money, less often felt that their career took precedence over their spouse's career, and more often played a major role in child-rearing. These differences were greater for female physicians than for male physicians. Men and women in dual-doctor families were similar to other physicians in the frequency with which they achieved career goals and goals for their children and with which they felt conflict between professional and family roles. Marriage to another physician had distinct benefits (P < 0.001) for both men and women, including more frequent enjoyment from shared work interests and higher family incomes. CONCLUSIONS: Men and women in dual-doctor families differed from other physicians in many aspects of their professional and family lives, but they achieved their career and family goals as frequently. These differences reflect personal choices that will increasingly affect the profession as more physicians marry physicians.

Cow hair allergen (Bos d 2) content in house dust: correlation with sensitization in farmers with cow hair asthma.

Farmers (N = 45) suffering from occupational cow hair asthma were visited at home to evaluate the concentration of cow hair major allergen Bos d 2 in the house dust and to correlate these results with measures of avoidance, degree of sensitization, clinical symptoms, and lung function. Bos d 2 was determined by rocket immunoelectrophoresis. In dust of tiles and linoleum Bos d 2 was difficult to detect, whereas dust samples of carpets often contained high concentrations of the allergen (50-520 micrograms/g fine dust). Bos d 2 levels were significantly higher when barn and living quarters were in the same building. Concentrations of cow hair-specific IgE were correlated with concentrations of Bos d 2 in house dust samples. A concentration of 20-29 micrograms Bos d 2 per gram of house dust could be established as threshold value for relevant IgE sensitization. Avoiding the barn is not a sufficient avoidance measure for cow hair asthmatics if the partner continues cattle farming. Cessation of cattle farming and avoiding the former barn results in a marked reduction in Bos d 2 concentration in living quarters, a decreased degree of sensitization, and a reduced symptom score. Farmers with cow hair asthma should avoid cattle and thoroughly clean all carpets in the living quarters to avoid continuous cow allergen exposure.

[Different threshold concentrations for sensitization by cattle hair allergen Bos d 2 in atopic and non-atopic farmers]. / Differente Schwellenwertkonzen-trationen für Sensibilisierungen durch das Rinderhaarallergen Bos d 2 bei atopischen und nicht-atopischen Landwirten.

Several threshold values for indoor allergens leading to IgE sensitization were proposed. Currently such values exists for allergens of house dust mite, cat, dog, and cockroach and cattle. A high sensitization is known as an important risk factor in the development of asthma. This study was undertaken to examine threshold values of major cow hair allergen Bos d 2 in the house dust of atopic and nonatopic cow hair asthmatic farmers. 45 patients with cow hair asthma were visited at their homes. House dust samples were taken from corridor, living room, and bedroom. The concentration of Bos d 2 was determined by means of rocket immunoelectrophoresis. Additionally, samples of venous blood were taken to demonstrate specific IgE towards cow epithelia by CAP-RAST. Five patients were excluded from further investigations because they have given up their cattle for less than 6 months. In 21 patients occurred typical atopic stigmata like infantil history of atopic eczema, hay fever or milk crust, while the other 19 subjects did not show an atopic diathesis. High sensitization towards cow epithelia (specific IgE > 0.7 kU/l in CAP-RAST) occurred significantly more often in atopics than in nonatopics. In atopic subjects the allergen concentrations leading to IgE sensitization amounted to 1-20 micrograms Bos d 2/g dust, whereas in nonatopics were found higher Bos d 2 threshold values (25-50 micrograms/g dust). The present study suggests that in nonatopic cow hair asthmatics high indoor Bos d 2 levels lead to IgE sensitization as well as the close contact to cattle.