Comprehension of written texts for the assessment of clinical competence and decision making in people with mild to moderate Alzheimer disease.

BACKGROUND: Clinical competence is the term used to describe an individual's capacity to express a choice regarding their participation in clinical procedures or experimental studies. Understanding the information provided is a prerequisite but consent forms are often lengthy and complicated. Alzheimer's disease patients may be vulnerable in written comprehension, due to cognitive deficits, but unfortunately to date, a specific evaluation of this ability is not included in periodical assessments. METHODS: One hundred thirty Italian patients with Alzheimer's disease were compared with 130 controls in a comprehension task involving a simplified informed consent form. Their performance in this task was compared with their performance with two other types of reading material (a testament and a history text). In addition, the performance of a subgroup of very mild patients in this test was compared with their performance in a widely used interview for the assessment of clinical competence (MacArthur Competence Assessment Tool for Clinical Research). RESULTS: Good sensitivity and specificity of the cut-offs identified consent form and the other texts as good instruments for evaluation of written comprehension. The comprehension of consent form may be compromised since the early stages of Alzheimer's disease. Nevertheless, a simplified, written text may help patients in comparison with interviews (MacCAT-CR). Better performance was correlated to the standard of education and better cognitive functions. CONCLUSION: Deficits regarding the comprehension of written texts and the consent form may be early in Alzheimer's disease patients and need to be investigated during periodical neuropsychological assessment. Comprehension may be facilitated by means of specific simplification strategies.

The ANT Home Care Model in Palliative and End-of-Life Care. An Investigation on Family Caregivers' Satisfaction with the Services Provided.

The World Health Organization plan for a Decade of Healthy Ageing 2020-2030 has established some priorities in the field of palliative and end-of-life care. It states that "people require non-discriminatory access to good-quality palliative and end-of-life care" and recommends the "implementation of strategies for the provision of information, training, respite and support for informal caregivers". The priorities described are in line with the home care services that National Tumor Assistance (ANT) Foundation has been providing in Italy. This 5-years investigation was designed to measure caregivers' satisfaction and determine what types of support services are associated with greater satisfaction. 5.441 family caregivers filled out autonomously a 6-item questionnaire at the end of home care assistance, focusing on the level of satisfaction with the social and health services received. The overall data indicate a high satisfaction rate for the home care assistance received. In particular, participants rate positively the assistance provided by healthcare professionals (physicians, nurses and psychologists). The most appreciated aspects of assistance are those ensuring a global management of patients and their families, whereas an area of deficiency emerged was the continuity of care, suggesting the importance to implement the networks between the health care facilities and home care services. The present investigation constitutes a mean to highlight the aspects associated with greater satisfaction and the ones perceived as less satisfactory by caregivers. Moreover, this research constitutes a crucial instrument to improve home care assistance provided by ANT ensuring the best quality of life for both patients and their families.

Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial.

OBJECTIVE: CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. DESIGN: This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0-100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. RESULTS: 213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P = 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ≥ 27.5 kg/m2, N = 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12-18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. CONCLUSIONS: Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2015-001136-37.

Awareness of cognitive deficits and clinical competence in mild to moderate Alzheimer's disease: their relevance in clinical practice.

Awareness of cognitive deficits and clinical competence were investigated in 79 mild to moderate Alzheimer's disease patients. Awareness was assessed by the anosognosia questionnaire for dementia, and clinical competence by specific neuropsychological tests such as trail making test-A, Babcock story recall test, semantic and phonemic verbal fluency. The findings show that 66 % of the patients were aware of memory deficits, while the 34 % were unaware. Deficit in awareness correlated with lower scores on the Mini Mental State Examination test that, in the score range from 24.51 to 30 and from 19.50 to 24.50, appeared to be a significant predictor of level of awareness. None of the AD patients had fully preserved clinical competence, only 7 patients (9 %) had partially preserved clinical competence and 72 patients (91 %) had completely lost clinical competence. All the patients with partially preserved clinical competence (9 %) were aware of their memory deficit. The study indicates that neuropsychological tests used for the assessment of executive functions are not suitable for investigating clinical competence. Therefore, additional and specific tools for the evaluation of clinical competence are necessary. Indeed, these might allow clinicians to identify AD patients who, despite their deficits in selected functions, retain their autonomy of choice as well as recognize those patients who should proceed to the nomination of a legal representative.

Leukotriene D4-induced activation of smooth-muscle cells from human bronchi is partly Ca2+-independent.

Cysteine-containing leukotrienes (cysteinyl-LTs) are potent bronchoconstrictors and play a key role in asthma. We found that histamine and LTD4 markedly constrict strips of human bronchi (HB) with similar efficacy. However, in human airway smooth-muscle (HASM) cells, LTD4, at variance with histamine, elicited only a small, transient change in intracellular calcium ion concentration. HASM cells express both Ca2+-dependent and -independent isoforms of protein kinase C (PKC) (i.e., PKC-alpha and PKC-alpha ). Western blot analysis showed that PKC-alpha is activated by histamine and, to a lesser extent, by LTD4, whereas only LTD4 translocates PKC-alpha. This translocation was specifically inhibited by the LTD4 antagonist pobilukast. Phorbol-dibutyrate ester (PDBu) (a PKC activator) contracted HB strips to the same extent in the presence as in the absence of extra- and intracellular Ca2+. In the absence of Ca2+, LTD4 contracted HB strips to the same extent as did PDBu, suggesting the involvement of a Ca2+-independent PKC in LTD4-mediated signal transduction. PDBu-induced desensitization and the PKC inhibitor H7 abolished the slow and sustained LTD4-triggered contraction of HB strips in the absence of Ca2+, although H7 did not greatly affect the response in the presence of the ion. Thus, in human airways, we identified a novel LTD4 transduction mechanism linked to bronchial smooth-muscle contraction, which is partly independent of Ca2+ and involves the activation of PKC-alpha.

Corneal epithelial VEGF and cytochrome P450 4B1 expression in a rabbit model of closed eye contact lens wear.

PURPOSE: The similar and overlapping activity of VEGF and the potent corneal-derived angiogenic eicosanoid 12(R)-HETrE calls for a study of the temporal relationship in the expression of these two autocoids. Since recent evidence suggests that hypoxia induces the expression of a CYP4B1 mRNA which might be involved in the conversion of arachidonic acid to 12(R)-HETrE, we determined its time-dependent expression and correlated it to that of VEGF mRNA in the rabbit model of closed eye contact lens-induced injury. METHODS: Rabbit eyes were fitted with contact lenses followed by a silk suture tarsorrhaphy. The anterior surface was analyzed at 2-, 4- and 7-days by slit lamp biomicroscopy, subjective inflammatory scoring and corneal pachymetry. Corneal epithelium was scraped and CYP4B1 and VEGF mRNA levels were measured by Southern hybridization of RT-PCR products amplified from a single cornea with specific primers. RESULTS: Corneal thickness and inflammatory scores increased in a time dependent manner in the model of closed eye contact lens induced hypoxic injury. Corneal epithelial CYP4B1 and VEGF mRNAs, as well as the production of the angiogenic eicosanoid, 12-HETrE, increased in a time-dependent manner and correlated with the in situ inflammatory response. CONCLUSIONS: The present study documents the increased expression of CYP4B1 isoform in the corneal epithelium during hypoxic injury in vivo. It also demonstrates the presence of VEGF mRNA in the corneal epithelium and its increased expression in this model of hypoxic injury. All together, the results of this study raise the possibility of interaction between these autocoids, VEGF and CYP4B1-12(R)-HETrE, in mediating the neovascularization response induced by the prolonged hypoxic state brought about by closed eye contact lens wear.

Effect of endogenous and exogenous prostaglandin E(2) on interleukin-1 beta-induced cyclooxygenase-2 expression in human airway smooth-muscle cells.

We studied the effect of endogenous and exogenous prostaglandin E(2) (PGE(2)), a metabolite of arachidonic acid through the cyclooxygenase (COX) pathway, on interleukin (IL)-1 beta-induced COX-2 expression, using primary cultures of human bronchial smooth-muscle cells (HBSMC). Treatment with exogenous PGE(2) resulted in enhanced expression of IL-1 beta-induced COX-2 protein and messenger RNA (mRNA) as compared with the effect of the cytokine per se. Inhibition of PGE(2) production with a nonselective COX inhibitor (flurbiprofen, 10 microM) resulted in a significant reduction in IL-1 beta- induced COX-2 expression, supporting a role of endogenous COX metabolites in the modulation of COX-2 expression. None of the experimental conditions used in the study affected the expression of constitutive cyclooxygenase (COX-1). Treatment with cycloheximide to inhibit translation, and with dexamethasone or actinomycin D to inhibit transcription, linked the effect of PGE(2) to the transcriptional level of COX-2 mRNA rather than to a potential effect on protein and/or mRNA stabilization. PGE(2) increased adenylate cyclase activity in a concentration dependent manner, and forskolin, a direct activator of adenylate cyclase, caused a marked increase in IL-1 beta-dependent COX-2, suggesting the existence of a causal relationship between the two events. The same results were observed with salbutamol, a bronchodilator that acts by increasing cyclic adenosine monophosphate. The effect of PGE(2) on COX-2 expression may contribute to the hypothesized antiinflammatory role of PGE(2) in human airways, providing a self-amplifying loop leading to increased biosynthesis of PGE(2) during an inflammatory event.

The effect of hypoxia on endogenous corneal epithelial eicosanoids.

PURPOSE: Injury to the corneal epithelium increases arachidonic acid (AA) metabolism through the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 pathways. The authors used the rabbit corneal organ culture model to demonstrate the effect of hypoxia on the endogenous formation of 12-hydroxy-5,8,11,14-eicosatetraenoic acid (12-HETE), 12-hydroxy-5,8,14-eicosatrienoic acid (12-HETrE), and prostaglandin (PG) E2 by the intact cornea in the absence of exogenously added cofactors or substrate. METHODS: Rabbit corneas were isolated and cultured for 24 hours in normoxia or hypoxia. After culture, PGE2 in media was quantitated by enzyme immunoassay. 12-HETE and 12-HETrE were extracted from culture media and corneal epithelium and quantitated by negative chemical ionization-gas chromatography-mass spectrometry. COX-1 and -2 protein expression in corneal epithelium was determined by Western blot. Acute (2 hours) COX activity in normoxia and hypoxia was determined as the conversion rate of [14C]AA to [14C]PGE2, quantitated through reverse-phase-high-performance liquid chromatography and radiodetection. RESULTS: In the media of cultured rabbit corneas, both 12-HETE and 12-HETrE were detected, with 12-HETrE levels being four times higher. Hypoxia did not significantly increase extracellular 12-HETE or 12-HETrE; however, it caused more than 90% inhibition of PGE2 synthesis. Intracellular 12-HETE and 12-HETrE were undetectable in normal corneas but increased to 7.7+/-1.3 and 2.2+/-0.4 ng/mg protein, respectively, after 24 hours in culture. Culture in hypoxia further increased intracellular 12-HETE threefold but had no additional effect on 12-HETrE. CONCLUSIONS: Hypoxia creates an environment in which epithelial COX activity is severely suppressed, whereas cytochrome P450-AA and/or 12-LOX metabolizing activity is maintained or enhanced. Additionally, the findings suggest that 12-HETE produced by the corneal epithelium acts intracellularly to promote corneal edema, whereas 12-HETrE acts in a paracrine manner to initiate an inflammatory cascade that can elicit neutrophil chemotaxis and neovascularization of the cornea.

Monoclonal anti-CD18 antibody prevents transcellular biosynthesis of cysteinyl leukotrienes in vitro and in vivo and protects against leukotriene-dependent increase in coronary vascular resistance and myocardial stiffness.

BACKGROUND: Cysteinyl leukotrienes (cys-LT) can constrict small and large vessels and increase vascular permeability. Formation of cys-LT arising from polymorphonuclear leukocytes (PMNL) and endothelial cell cooperation (transcellular synthesis) led to the hypothesis that PMNL-endothelial cell adhesion may represent a key step toward the formation of vasoactive cys-LT. METHODS AND RESULTS: We studied the effect of pretreatment with a monoclonal antibody directed against the CD18 subunit of PMNL beta(2)-integrin on the synthesis of cys-LT in a PMNL-perfused isolated rabbit heart in vitro and in a model of permanent ligature of the left descending coronary artery in the rabbit in vivo. Challenge of PMNL-perfused rabbit hearts with formyl-met-leu-phe (0.3 micromol/L) caused synthesis of cys-LT and increase in coronary perfusion pressure that were prevented by the anti-CD18 antibody. Similar results were obtained with the use of A-23187 (0.5 micromol/L) as a challenge. Persistence of PMNL-associated myeloperoxidase activity in the perfusion buffer was observed in the presence of the anti-CD18 antibody, indicating decreased PMNL infiltration. Coronary artery ligature in vivo increased urinary excretion of leukotriene E(4), supporting the activation of the 5-lipoxygenase pathway during experimental acute myocardial infarction. Pretreatment with the anti-CD18 antibody (1 mg/kg) prevented the increase in leukotriene E(4) excretion. CONCLUSIONS: These data support the importance of adhesion in promoting cys-LT formation, originating from PMNL-endothelial cell cooperation, and contributing to myocardial stiffness and increased coronary resistance.

Regulation of cyclooxygenase-2 by hypoxia and peroxisome proliferators in the corneal epithelium.

Hypoxic injury provokes inflammation of many tissues including the ocular surface. In rabbit corneal epithelial cells, both peroxisome proliferator-activated receptor (PPAR)-inducible cytochrome P450 4B1 and cyclooxygenase-2 (COX-2) mRNAs were increased by hypoxia. PPAR alpha and beta but not gamma mRNAs were detected in these cells. The PPAR activator, WY-14,643 increased COX-2 expression. Similarly, non-steroidal anti-inflammatory drugs with the ability to activate PPARs induced COX-2 independently of prostaglandin synthesis inhibition. COX-2 protein overexpression by hypoxia and PPAR activation was not associated with a parallel increase in prostaglandin E(2) accumulation. However, the enzyme regained full catalytic activity when: 1) hypoxic cells were re-exposed to normoxic conditions in the presence of heme and arachidonic acid, and 2) WY-14,643-treated cells were depleted of intracellular GSH. Consistent with previous observations showing that the corneal production of cytochrome P450-derived inflammatory eicosanoids is elevated by hypoxia and inflammation, the current data suggest that hypoxic injury is a model of inflammation in which molecules other than COX-derived arachidonic acid metabolites play a major proinflammatory role. This study also suggests that increased cellular GSH may be the mechanism responsible for the characteristic dissociation of PPAR-induced COX-2 expression and activity. Moreover, we provide new insights into the commonly observed lack of efficacy of classical non-steroidal anti-inflammatory drugs in the treatment of hypoxia-related ocular surface inflammation.

Hypoxia-induced production of 12-hydroxyeicosanoids in the corneal epithelium: involvement of a cytochrome P-4504B1 isoform.

The corneal epithelium metabolizes arachidonic acid by a cytochrome P-450 (CYP)-mediated activity to 12-hydroxy-5,8,11, 14-eicosatetraenoic acid (12(R)-HETE) and 12-hydroxy-5,8, 14-eicosatrienoic acid (12(R)-HETrE ). Both metabolites possess potent inflammatory properties, with 12(R)-HETrE being a powerful angiogenic factor, and they assume the role of inflammatory mediators in hypoxia- and chemical-induced injury in the cornea in vivo and in vitro. We used a model of corneal organ culture that exhibits hypoxia-induced epithelial CYP-dependent 12(R)-HETE and 12(R)-HETrE synthesis for isolating, identifying, and characterizing the CYP protein responsible for these eicosanoid syntheses. Northern analysis revealed the presence of a CYP4A-hybridizable mRNA, the levels of which were increased after hypoxia. Reverse transcription-polymerase chain reaction analysis with primers specific for the CYP4A family led to the isolation of a 671-base pair fragment with a 98.8% sequence homology to the rabbit lung CYP4B1 isoform, of which the levels in the corneal epithelium were greatly increased under hypoxic conditions. Moreover, phenobarbital, an inducer of hepatic CYP4B1 in the rabbit, also induced 12-HETE and 12-HETrE synthesis. Antibodies against CYP4B1, but not against CYP4A1, inhibited hypoxia-, clofibrate-, and phenobarbital-induced 12-HETE and 12-HETrE synthesis. These results suggest the involvement of a CYP4B1 isoform in the corneal epithelial synthesis of these eicosanoids in response to hypoxia.

Cyclo-oxygenase-2 mediates P2Y receptor-induced reactive astrogliosis.

Excessive cyclo-oxygenase-2 (COX-2) induction may play a role in chronic neurological diseases characterized by inflammation and astrogliosis. We have previously identified an astroglial receptor for extracellular nucleotides, a P2Y receptor, whose stimulation leads to arachidonic acid (AA) release, followed, 3 days later, by morphological changes resembling reactive astrogliosis. Since COX-2 may be upregulated by AA metabolites, we assessed a possible role for COX-2 in P2Y receptor-mediated astrogliosis. A brief challenge of rat astrocytes with the ATP analogue alpha,beta-methylene ATP (alpha,beta(me)ATP) resulted, 24 h later, in significantly increased COX-2 expression. The selective COX-2 inhibitor NS-398 completely abolished alpha,beta(me)ATP-induced astrocytic activation. Constitutive astroglial COX-1 or COX-2 did not play any role in purine-induced reactive astrogliosis. PGE2, a main metabolite of COX-2, also induced astrocytic activation. These data suggest that a P2Y receptor mediates reactive astrogliosis via induction of COX-2. Antagonists selective for this receptor may counteract excessive COX-2 activation in both acute and chronic neurological diseases.

Cyclooxygenase-2 and synthesis of PGE2 in human bronchial smooth-muscle cells.

The purpose of this study was to determine the mechanism of enhanced prostaglandin synthesis in cultured human bronchial smooth-muscle cells challenged with interleukin-1 beta (IL-1 beta). Cells were incubated with IL-1 beta (10 to 50 U/ml) for 0 to 24 h. Prostaglandin E2 (PGE2) production was evaluated through the conversion of exogenous (14C)-arachidonic acid and specific enzyme immunoassay of endogenous products. IL-1 beta enhanced PGE2 formation in a concentration- and time-dependent manner, reaching its peak at 6 to 8 h and fading at 18 to 24 h. Immunoblot analysis showed that the inducible cyclooxygenase enzyme (COX-2) was expressed only in IL-1 beta treated cells, whereas the constitutive isoform of cyclooxygenase (COX-1) remained unaltered. COX-2 expression and PGE2 formation were inhibited by dexamethasone (2 microM), cycloheximide (10 microM), and IL-1-receptor antagonist (IL-1 ra) (250 ng/ml), independently. PGE2 synthesis was significantly reduced by compound SC-58125, a specific COX-2 inhibitor. The close parallelism between the kinetics of COX-2 protein expression and PGE2 accumulation, as well as the constitutive nature of COX-1 isoform, indicate that IL-1 beta-driven PGE2 formation in human bronchial smooth-muscle cells is mediated by de novo expression of COX-2 enzyme.

Nitric oxide modulation of transcellular biosynthesis of cys-leukotrienes in rabbit leukocyte-perfused heart.

1. We have studied the role of nitric oxide (NO) in the regulation of the transcellular biosynthesis of sulphidopeptide leukotrienes (cys-LT) generated upon neutrophil-vascular wall interactions and their functional consequences, in the spontaneously beating, cell-perfused, heart of the rabbit. 2. Hearts were perfused under recirculating conditions (50 ml) with 5 x 10(6) purified human neutrophils (PMNL), and challenged with 0.5 microM A-23187 for 30 min. Coronary perfusion pressure (CPP) and left-ventricular end-diastolic pressure (LVEDP) were monitored. Cys-LT formation was measured by reversed phase high performance liquid chromatography (h.p.l.c.) and u.v. spectral analysis. Myeloperoxidase (MPO) enzyme activity, assayed in aliquots of the recirculating buffer, was used as a marker of PMNL, adhesion to the coronary endothelium. 3. Basal CPP and LVEDP values averaged 45 +/- 1.4 mmHg and 5 +/- 0.1 mmHg, respectively; A-23187 triggered an increase in CPP (134 +/- 9 mmHg, at 30 min) which was significantly attenuated by pretreatment with L-arginine, 100 microM (90 +/- 3 mmHg, at 30 min). Pretreatment with NG-monomethyl-L-arginine, 10 microM (L-NMMA), induced a marked increase in CPP (290 +/- 40 mmHg, at 20 min) and in LVEDP (47 +/- 16 mmHg), so pronounced that it caused cardiac arrest in systole in 5 out of 6 hearts and these were prevented by L-arginine, 100 microM, (CPP 115 +/- 10 mmHg, LVEDP 6 +/- 1.1 mmHg, at 30 min). 4. The increase in CPP was accompanied by the release of cys-LT in the circulating buffer, which was reduced significantly by L-arginine. Pretreatment with L-NMMA, caused a marked rise in cys-LT concentrations which was prevented by L-arginine. 5. Neither L-arginine nor L-NMMA affected directly the A-23187-induced arachidonic acid (AA) metabolism in isolated PMNL alone. 6. Pretreatment with L-NMMA caused a prompt drop in myeloperoxidase (MPO), activity, suggesting rapid adhesion of PMNL to the coronary wall; this effect was significantly blunted by L-arginine. 7. This study suggests that NO provides cardioprotection in an organ model of transcellular metabolism of cys-LT by preventing PMNL adhesion to the coronary intima.

The polymorphonuclear leukocyte: a cell tuned for transcellular biosynthesis of cys-leukotrienes.

Sulfidopeptide leukotrienes (cysLT) are potent vasoactive mediators that can constrict coronary vessels and alter caliber of the microcirculation. They can be formed "in situ" via a peculiar type of cell communication termed "transcellular biosynthesis" whereby donor cells (polymorphonuclear leukocytes, PMNL) feed acceptor cells (endothelial cells, EC) the unstable epoxide intermediate leukotriene A4 for further metabolism to cysLT. We have investigated the relative amount of leukotriene A4 that is synthesized by PMNL and made available for transcellular biosynthesis. This has been accomplished by measuring the relative amounts of enzymatic vs non-enzymatic leukotriene A4-derived metabolites after challenge with the Ca(2+)-ionophore A23187, using PMNL suspensions at different concentrations. Non-enzymatic leukotriene A4-derived metabolites were used as a quantitative index of the amount of leukotriene A4 released into the extracellular milieu. In human, as well as in bovine PMNL, the relative amounts of non-enzymatic vs enzymatic leukotriene A4-derived metabolites increased with decreasing cell concentrations. By diminishing possible cell-cell interactions via increased dilution, it is calculated that approx. 60% of leukotriene A4 synthesized is released from the PMNL. These data provide evidence that, in PMNL, transfer of leukotriene A4 to neighbouring acceptor cells is taking place as a predominant mechanisms of cell communication.

[Obstructive azoospermia and malformations of seminal tract]. / Azoospermia ostruttiva e malformazioni della via seminale.

About 10% of the cases of male infertility is represented by the obstruction of the seminal tract, which may be congenital or secondary to inflammatory events or surgery. The most frequent obstructive malformation of the seminal tract is the bilateral agenesia of the vas deferens. Such malformation is typical of the cystic fibrosis (CF), an autosomal recessive disorder determining chronic respiratory infections with bronchiectasia, and pancreatic failure. Recently the defective gene responsible for CF has been identified on the long arm of the chromosome 7. Congenital bilateral absence of the vas deferens (CBAVD) may be present in otherwise healthy males without clinical evidence of CF. Genetics studies demonstrated that most CBAVD display at least one detectable CF mutation, therefore this disease can be considered as an incomplete clinical form of CF. With the realization that a man with CBAVD may have CF, albeit a genital form, considerable care is required not only to document his specific mutations, but also to test his partner for CF mutations to evaluate the risk that their child would have CF. The association of chronic suppurating respiratory disease with obstructive azoospermia characterizes also the Young's syndrome. In this disease the obstruction could possibly be the result of defective epididymal sperm transport, related to an abnormality in the mucus. Despite some clinical common aspects, CF and Young's syndrome are two distinct entity. In fact, no CF mutations have been demonstrated in Young's syndrome. Congenital obstructive abnormalities of the vas deferens and epididymis are often associate to cryptorchidism (36-68% of the cases) and to patent processus vaginalis. The degree of testicular retention and processus vaginalis closure correlates well with the incidence of associated epididymal defects. Rare causes of congenital obstructive azoospermia are represent by the cyst of Müllerian or Wolffian origin. An obstruction to the progression of the sperm along the seminal tract can also be present in complex malformations, such as pseudohermaphroditism in which the infertility has a multifactorial etiology.

Thumb-pointing is humans after damage to somatic sensory cortex.

Three patients with a severe somatosensory deficit consequent on damage of the right somatosensory cortices were required, while blindfolded, to point with their insensate thumb to select positions on the other left fingers. Given the absence of feedback, the motor performance of the insensate thumb appeared grossly impaired in all patients. However, all patients attained end-points with an accuracy greater than chance. This result suggests that spatial accuracy may not rely entirely on sensory feedback. A good accuracy of pointing was evinced also in potentially facilitating conditions where somatosensory and motor cues coming from the intact side during simultaneous movement of both thumbs, vision of stimulated point and final thumb position, and visuomotor imagery were available. Furthermore, in one patient, the accuracy of the insensate thumb in cued conditions was higher than in a reference baseline condition, thus indicating that motor and cognitive cues can help the motor performance of patients with cortical somatosensory lesions.

Phantom lower limb as a perceptual marker of neural plasticity in the mature human brain.

Three lower limb amputees, who reported phantom sensations, referred somatic stimuli delivered to skin regions proximal to the stump to select points on the phantom limb. Stimuli on the rectum and anus (e.g. during defecation) and on genital areas (e.g. during sexual intercourse) induced analogous, although less precise, mislocation to the phantom limb. Although the representation of the stump in the somatosensory pathway is lateral to that of the amputated lower limb, both anus and genitals are mapped medially to the areas formerly subserving the amputated lower limb. Therefore the mislocalization phenomenon can be considered as a perceptual landmark of new functional connections between the deprived areas and the adjacent ones, thus suggesting a dynamic neural remodelling in the mature nervous system, which was previously considered as a static entity.