Identification and management of poor response to growth‐promoting therapy in children with short stature

Growth hormone (GH) is widely prescribed for children with short stature across a range of growth disorders. Recombinant human (rh) insulin‐like growth factor‐1 (rhIGF‐1) therapy is approved for severe primary IGF‐I deficiency – a state of severe GH resistance. Evidence is increasing for an unacceptably high rate of poor or unsatisfactory response to growth‐promoting therapy (i.e. not leading to significant catch up growth) in terms of change in height standard deviation score (SDS) and height velocity (HV) in many approved indications. Consequently, there is a need to define poor response and to prevent or correct it by optimizing treatment regimens within accepted guidelines. Recognition of a poor response is an indication for action by the treating physician, either to modify the therapy or to review the primary diagnosis leading either to discontinuation or change of therapy. This review discusses the optimal investigation of the child who is a candidate for GH or IGF‐1 therapy so that a diagnosis‐based choice of therapy and dosage can be made. The relevant parameters in the evaluation of growth response are described together with the definitions of poor response. Prevention of poor response is addressed by discussion of strategy for first‐year management with GH and IGF‐1. Adherence to therapy is reviewed as is the recommended action following the identification of the poorly responding patient. The awareness, recognition and management of poor response to growth‐promoting therapy will lead to better patient care, greater cost‐effectiveness and increased opportunities for clinical benefit.     

Reproductive factors and clinical features of Parkinson's disease

BackgroundLiterature suggests that sex steroid hormones may modify the risk for Parkinson's disease (PD). We investigated the potential effect of reproductive factors on the clinical features of idiopathic PD (IPD) patients.MethodsAll IPD female patients admitted to and evaluated at our Institute over a 12-month period were included in the present cross-sectional study. We investigated the effect of the following parameters by multivariate linear regression analysis: age at menarche, age at menopause, length of fertile life, duration of exposure to endogenous estrogens and cumulative length of pregnancies, use of contraceptives and hormonal replacement therapy.ResultsIn total, 579 patients were evaluated and 497 reported menopause before PD onset. In this population, age at PD onset was positively associated with age at menarche and at menopause, length of fertile life and duration of estrogen exposure. Moreover, UPDRS motor score was inversely associated with age at menopause, length of fertile life and duration of estrogen exposure. Increasing age at menarche was also associated with predominant resting tremor at PD onset. In models refitted on patients with early PD (disease duration <5 years; N = 226) all the associations found were confirmed. The relationship between surrogates of estrogen exposure and UPDRS motor score actually became more significant.ConclusionsOur observations support the concept that hormonal exposure of the nigro-striatal network during life may influence its susceptibility to degenerative stimuli in later life, but the association does not seem to be unique? unidirectional. In particular, increased severity of PD signs correlates with shorter duration of estrogen exposure. The underlying mechanisms need to be clarified.     

The p.A382T TARDBP gene mutation in Sardinian patients affected by Parkinson's disease and other degenerative parkinsonisms

Based on our previous finding of the p.A382T founder mutation in ALS patients with concomitant parkinsonism in the Sardinian population, we hypothesized that the same variant may underlie Parkinson's disease (PD) and/or other forms of degenerative parkinsonism on this Mediterranean island. We screened a cohort of 611 patients with PD (544 cases) and other forms of degenerative parkinsonism (67 cases) and 604 unrelated controls for the c.1144G > A (p.A382T) missense mutation of the TARDBP gene. The p.A382T mutation was identified in nine patients with parkinsonism. Of these, five (0.9 % of PD patients) presented a typical PD (two with familiar forms), while four patients (6.0 % of all other forms of parkinsonism) presented a peculiar clinical presentation quite different from classical atypical parkinsonism with an overlap of extrapyramidal–pyramidal–cognitive clinical signs. The mutation was found in eight Sardinian controls (1.3 %) consistent with a founder mutation in the island population. Our findings suggest that the clinical presentation of the p.A382T TARDBP gene mutation may include forms of parkinsonism in which the extrapyramidal signs are the crucial core of the disease at onset. These forms can present PSP or CBD-like clinical signs, with bulbar and/or extrabulbar pyramidal signs and cognitive impairment. No evidence of association has been found between TARDBP gene mutation and typical PD.     

The Influence of Death Exposure on Suicidal Thoughts and Behaviors

The present study investigated the relationship between exposure to both suicidal and non-suicidal deaths and current suicidal ideation and suicide attempt history among urban college students. Three hundred and ninety-six (n = 396) undergraduate students attending an urban university completed a series of questionnaires assessing their exposure to death (including suicide), suicide attempt history, and current level of suicidal ideation. Exposure to suicide and non-suicidal death were not related to current suicidal ideation; however, students who had made a suicide attempt were more likely to have been exposed to a death by suicide or acute disease. The findings of this study suggest that exposure to death by suicide or acute disease increased the likelihood a student made a past suicide attempt.     

Experimental Study of the Course of Threshold Current,Voltage and Electrode Impedance During Stepwise Stimulation From the Skin Surface to the Human Cortex

BackgroundTranscranial electric stimulation as used during intraoperative neurostimulation is dependent on electrode and skull impedances.ObjectiveThreshold currents, voltages and electrode impedances were evaluated with electrical stimulation at 8 successive layers between the skin and the cerebral cortex.Patients and MethodsData of 10 patients (6f, 53 ± 11 years) were analyzed. Motor evoked potentials were elicited by constant current stimulation with corkscrew type electrodes (CS) at C3 and C4 in line with standard transcranial electric stimulation. A monopolar anodal ball tip shaped probe was used for all other measurements being performed at the level of the skin, dura and cortex, as well as within the skull by stepwise performed burr holes close to C3 resp. C4.ResultsAverage stimulation intensity, corresponding voltage and impedance for muscle MEPs at current motor threshold (CMT) were recorded: CS 54 ± 23 mA (mean ± SD), 38 ± 21 V, 686 ± 146 Ω; with the monopolar probe on skin 55 ± 28 mA, 100 ± 44 V, 1911 ± 683 Ω and scalp 59 ± 32 mA, 56 ± 28 V, 1010 ± 402 Ω; within the skull bone: outer compact layer 33 ± 23 mA, 91 ± 53 V, 3734 ± 2793 Ω; spongiform layer 33 ± 23 mA, 70 ± 44 V, 2347 ± 1327 Ω; inner compact layer (ICL) 28 ± 19 mA, 48 ± 23 V, 2103 ± 1498 Ω; on dura 25 ± 12 mA, 17 ± 12 V, 643 ± 244 Ω and cortex 14 ± 6 mA, 11 ± 5 V, 859 ± 300 Ω. CMTs were only significantly different for CS (P = 0.02) and for the monopolar probe between the cortex and ICL (P = 0.03), scalp (P = 0.01) or skin (P = 0.01) and between ICL and CS (P ≤ 0.01) or skin (P ≤ 0.01).ConclusionThe mean stimulation current of the CMT along the extracranial to intracranial anodal trajectory followed a stepwise reduction. VMT was strongly dependent on electrode impedance. CMT within the skull layers was noted to have relative strong shunting currents in scalp layers.     

Novel INF2 mutation p. L77P in a family with glomerulopathy and Charcot-Marie-Tooth neuropathy

Background

Mutations in inverted formin, FH2, and WH2 domain containing (INF2) are common causes of dominant focal segmental glomerulosclerosis. INF2 encodes a member of the diaphanous-related formin family, which regulates actin and microtubule cytoskeletons. Charcot-Marie-Tooth neuropathy (CMT) is a group of inherited disorders affecting peripheral neurons. Many reports have shown that glomerulopathy can associate with CMT. However, it has been unclear whether these two processes in the same individual represent one disorder or if they are two separate diseases.

Case diagnosis/treatment

Recently, INF2 mutations were identified in 12 of 16 patients with CMT-associated glomerulopathy, suggesting that these mutations are a common cause of the dual phenotype. In this study, we report two cases of CMT-associated glomerulopathy that both showed INF2 mutations. A novel INF2 mutation, p. L77P, was identified in a family in which the dual phenotype was inherited in a dominant fashion. The pathogenic effect of p. L77P was proposed using a structural homology model. In addition, we identified a patient with a sporadic CMT-associated glomerulopathy carrying a known INF2 mutation: p. L128P.

Conclusions

Our study confirms the link between INF2 mutations and CMT-associated glomerulopathy and widens the spectrum of pathogenic mutations.     

Asymmetry and freezing of gait in parkinsonian patients

It has been hypothesized that freezing of gait (FOG) in parkinsonian patients (PD) might be triggered by a breakdown in the normal symmetry of gait. In this study, we evaluated the relationship between asymmetry of gait and FOG and the effects of intensive treadmill treatment on asymmetry. We studied 30 patients with (FOG+) and 30 without (FOG?) freezing in “on” stage. Patients underwent a 4-week rehabilitation treatment using a treadmill with auditory and visual cues and were evaluated at enrolment and at the end of rehabilitation. Outcome measures were gait speed, stride length, asymmetry of gait, Six-minute walking test (6MWT), Unified Parkinson’s Disease Rating Scale (UPDRS) II–III, Berg Balance Scale, Timed Up and Go Test, comfortable-fast gait speeds, freezing of gait questionnaire (FOGQ). At enrolment, no differences in gait parameters were observed between the two groups, which differed only in UPDRS_II and BBS. Both FOG+ and FOG? patients spent more time on the left foot (time on left/time on right foot 1.37, p = 0.002, 1.18, p = 0.016, respectively). Rehabilitation determined a homogeneous improvement in both groups of patients for all variables except UPDRS_II and balance, for which a better improvement was observed in FOG+ patients. The improvement in FOGQ in FOG+ patients was significantly correlated to the improvement in asymmetry of gait (Spearman R = 0.46, p = 0.013). Our data support a direct involvement of the asymmetry of gait in the development of FOG in PD. Treadmill training is effective in improving gait and balance in PD FOG+ patients and this might be related to a reduction of asymmetric gait.