The use of preparations of urinary bladder smooth muscle for bioassay of and discrimination between polypeptides

Summary Eleven polypeptides, two prostaglandins and three amines were assayed, in parallel, by measurement of their spasmogenic effect on the isolated urinary bladder of eight animal species, the in situ bladder of three species and the isolated ureter of three species. Several of the smooth muscle preparations examined proved to be sensitive and suitable test-objects for the quantitative bioassay of different peptides. At the same time they appeared to be useful for discriminating not only between peptides belonging to different groups, but also between members of the same peptide family. It is tentatively suggested that biogenic peptides may interfere in the physiological control of motility and tone of the urinary tract smooth muscle.Supported by grants from the Consiglio Nazionale delle Ricerche, Roma.     

Evidence of a genetic marker associated with early onset in Friedreich's ataxia

We evaluated the association between age at onset of Friedreich's ataxia and alleles of two restriction fragment length polymorphisms (RFLP) at D9S15 and D9S5 in the 9gl3–9g21.1 region. We studied 65 Italian patients from 49 families. Age at onset was not normally distributed in our patients, suggesting allelic heterogeneity. Patients homozygous for allele 1 ofMspI RFLP detected by probe MCT112 at D9S15 (M1) had an earlier onset (mean 9.3, SD 3.4 years) than patients homozygous for allele 2 (M2; mean 12.1, SD 4.3). Heterozygotes had an onset age similar to that of the M2 homozygotes. These findings suggest that the M1 allele might be a marker of one allelic early-onset Friedreich's ataxia mutation.     

Impulse coding of ramp currents intracellularly injected into pyramidal tract neurones

Summary Relationships between the repetitive discharge and dynamic aspects of the input were analyzed in pyramidal tract neurones of the cat. Inputs were intracellularly injected currents reaching a steady level after ramps of different slopes (from 0.02 to 1.5 nA ms^–1). Output was the instantaneous frequency of the discharge. During the transient phase, instantaneous frequency appeared to be related both to the velocity of rise and to the intensity of the stimulating current. The dynamic component of the cell response was estimated by subtraction of the intensity-bound component (derived from the steady-state response to current steps). After subtraction, the instantaneous frequency of interspike intervals following the first one became proportional to the ramp slope. The instantaneous frequency of the first interval also increased with the current slope, but at a lower rate than the frequency of other intervals. Moreover its dynamic component virtually stopped growing when the ramp slope exceeded 0.3–0.5 nA ms^–1.     

Ocular pharmacokinetics of dapiprazole

Dapiprazole is a drug having specific alpha 1 adrenergic blocking properties. Following topical instillation on the eye, it crosses the corneal epithelium reaching high concentrations in the ocular tissue and producing a prompt miotic and hypotensive effect. The high concentration ratio between ciliary bodies and iris versus aqueous humor suggests a peculiar affinity for these structures containing adrenoceptors of the alpha type. The very low concentrations in the plasma, as compared to those after systemic administration, and in the fellow eye indicate that the systemic absorption is negligible.     

Subthreshold psychiatric disorders in primary care: prevalence and associated characteristics

BACKGROUND: The authors analyse the prevalence of subthreshold psychiatric disorders in primary care and their association with the patient's health perception, disability in daily activities and psychological distress. METHODS: Five-hundred and fifty-four primary care patients who completed a two-phase study were administered the Composite International Interview for Primary Health Care (CIDI-PHC) and other self-report measures. Unweighted and weighted prevalence estimates were obtained for ICD-10 formal disorders and subthreshold disorders defined by specific operational criteria. The impact of subthreshold disorders on health perception, disability in daily activities and psychological distress was analysed by using multiple regression models. RESULTS: The overall prevalence of subthreshold disorders exceeded that of ICD-10 disorders. Subjects with subthreshold disorders reported levels of psychological distress, disability in daily activities and perceived health comparable to those of patients with full-fledged ICD-10 disorders. When we analysed the associated health characteristics of individual subthreshold disorders, we found that each subthreshold disorder was characterized by poorer health perception, after adjusting for comorbidity with defined disorders and physical illness, age and gender. Disability in daily activities was increased in individuals with subthreshold depression and agoraphobia. LIMITATIONS: The number of cases with subthreshold panic and somatization is very small and does not allow one to draw any definite conclusions on their associated characteristics. To reduce non-response bias related to sampling design and refusals, adjusted sampling weights were computed. Since the study design in Bologna and Verona was different and Bologna patients scoring <4 on the General Health Questionnaire were not interviewed, individuals with minimal distress come from the Verona sample alone. CONCLUSIONS: Because of the prevalence and associated characteristics of subthreshold disorders, primary care physicians should attach adequate importance to the patient's perceived poor health, distress and inability to fulfil daily tasks. The clinical relevance of subthreshold disorders has also potential implications for ongoing revisions of classification systems.     

Typologies of anxiety, depression and somatization symptoms among primary care attenders with no formal mental disorder.

BACKGROUND: Typologies of anxiety, depression and somatization symptoms were investigated in individuals with no formal mental disorders, making no a priori assumptions about symptom distribution and inter-relationship. METHOD: The subjects were 1617 adult primary care attenders from the WHO Collaborative Project on Psychological Problems in General Health Care, with at least three symptoms of anxiety, depression and/or somatization, but with no formal ICD-10 disorders. Analyses were based on the grade of membership model, a multivariate statistical procedure exploring indistinct boundaries between disease categories and preserving the heterogeneity of clinical picture within each category. RESULTS: Six prototype categories (or pure types) best described the structure of symptoms included in analyses. Pure type I included the full set of somatization symptoms. Pure type II was characterized by most anxiety and depression symptoms. Pure type III resembled generalized anxiety disorder. Pure type IV consisted of individuals reporting sporadic symptoms of anxiety, depression or somatization. Pure type V defined individuals with sleep problems. Finally, pure type VI was characterized by anxiety symptoms, including panic-like symptoms. CONCLUSIONS: These findings provide support to the existence of a mixed anxiety-depression category crossing the diagnostic boundaries of current anxiety and depression disorders. Moreover, criteria of anxiety and somatization disorders may be re-examined to assess whether lower diagnostic thresholds can be identified that both preserve the symptom profile and clinical features of current diagnostic categories and allow for a better characterization of individuals with substantial psychopathology though not meeting the high symptom thresholds required for a diagnosis of formal mental disorders.     

Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC)

Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in KCNQ2 and KCNQ3, two genes encoding for potassium channel subunits. A large family with nine members affected by BFNC is described in the present study. All affected members of this family carry a novel deletion/insertion mutation in the KCNQ2 gene (c.761_770del10insA), which determines a premature truncation of the protein. In addition, in the family of the proposita's father, a novel sequence variant (c.2687A>G) in KCNQ3 leading to the p.N821S amino acid change was detected. When heterologously expressed in Chinese hamster ovary cells, KCNQ2 subunits carrying the mutation failed to form functional potassium channels in homomeric configuration and did not affect channels formed by KCNQ2 and/or KCNQ3 subunits. On the other hand, homomeric and heteromeric potassium channels formed by KCNQ3 subunits carrying the p.N821S variant were indistinguishable from those formed by wild-type KCNQ3 subunits. Finally, the current density of the cells mimicking the double heterozygotic condition for both KCNQ2 and KCNQ3 alleles of the proband was decreased by approximately 25% when compared to cells expressing only wild-type alleles. Collectively, these results suggest that, in the family investigated, the KCNQ2 mutation is responsible for the BFNC phenotype, possibly because of haplo-insufficiency, whereas the KCNQ3 variant is functionally silent, a result compatible with its lack of segregation with the BFNC phenotype.