Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50–70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20–100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human ( C2CD6 , C7orf61 , CCDC62 , CCIN , DNAH17 , GGN , PICK1 , SPATA16 , and ZPBP1 ). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.

Background: We investigated the long-term effects of continuous subcutaneous insulin infusion (CSII) on glucose control and microvascular complications in patients with type 1 diabetes (T1D). Methods: A total of 157 patients (59 M/98 W; age 39.1 ± 14.8 years) with T1D who switched from multiple daily injections to CSII and used CSII for at least one year were included. HbA1c levels and status of microvascular complications before and while under CSII were analyzed, retrospectively. Results: The follow-up period was 4.0 ± 1.5 years. HbA1c significantly decreased from 8.4 ± 1.3 to 7.7 ± 1.3% (68 ± 14 to 61 ± 14 mmol/mol) after 1-year CSII and remained lower than pre-CSII levels during four years. Patients with pre-CSII HbA1c >8.0% (64 mmol/mol) showed significant improvement of HbA1c for four years, while those with pre-CSII HbA1c <8.0% showed no significant change. The prevalence of retinopathy, albuminuria, and chronic kidney disease (CKD) were respectively 39%, 12%, and 9% at CSII initiation. During follow-up, the incidence of retinopathy, albuminuria, and CKD were 3.6, 2.5 and 1.4/100 patient-years. Onset or progression of retinopathy occurred in 16 (27.1%) patients with diabetes duration >15 years, and in three (4.3%) patients with diabetes duration <15 years (P < .01). Conclusion: CSII was effective in improving HbA1c for up to four years, specifically in patients with HbA1c >8% (64 mmol/mol) prior to CSII. Incidence and progression rates of retinopathy and albuminuria were low, particularly in patients with a diabetes duration <15 years at CSII initiation. These results argue for not delaying a proposal of CSII initiation in T1D with sustained HbA1c >8% (64 mmol/mol).

Nous avons évalué le contrôle glycémique et l'incidence des complications microangiopathiques sous pompe à insuline chez des patients diabétiques de type 1 (DT1) suivis durant 3 à 6 ans. 157 patients (59H/98F) DT1 ont été initiés à la pompe à insuline et suivis pendant 4,0 ± 1,5 ans. À l'initiation, l'âge était de 39,1 ± 14,8 ans, la durée du diabète de 17,7 ± 10,6 ans, l'IMC de 24,0 ± 1,3 kg/m2 et l'HbA1c de 8,4 ± 1,3 % sous analogues de l'insuline. La prévalence de la rétinopathie (RP) était de 39 %, de l'albuminurie > 30 mg/24 h (A) de 12 % et de l'insuffisance rénale (IR, clairance de la créatinine < 60 ml/mn) de 9 %. L'HbA1c et les complications microangiopathiques ont été analysées au terme de chaque année de traitement. Sur les 157 patients, 11 (7 %) sont revenus sous multi-injections, 4 ont évolué vers une pompe implantée, une greffe rein-pancréas ou une greffe d'îlots, 28 (18 %) ont été perdus de vue. L'HbA1c a baissé significativement après 1 an (7,7 ± 1,3 %, p < 0,01), avec un maintien de l'amélioration sur 5 ans (p < 0,01). La réduction de l'HbA1c a été significative quand l'HbA1c initiale était > 8 % (p < 0,01), mais pas quand elle était < 8 %. L'incidence de la RP a été de 3,6 pour 100 années-patients (%A-P), mais significativement moindre (1,5 % A-P, p < 0,01) quand la durée du diabète était < 15 ans à l'initiation. L'incidence de l'aggravation de la RP était de 6,9 % A-P, et significativement supérieure en cas de forme proliférante initiale (p < 0,04). L'incidence de A a été de 2,5 % A-P, mais tendait à être moindre (1,1 % A-P, p = 0,07) quand la durée du diabète était < 15 ans à l'initiation. L'incidence de l'IR était de 1,4 % A-P. Notre étude montre le bénéfice durable sur le contrôle glycémique de la pompe à insuline, associé à une faible incidence des complications rétiniennes et rénales pour les patients ayant moins de 15 ans de diabète à l'initiation. Ces résultats plaident pour ne pas retarder l'initiation à la pompe chez les patients dont l'HbA1c excède 8 %.

Reiterated catheter obstructions thwart improved diabetes control with continuous peritoneal insulin infusion (CPII) from implantable pumps (1). Occlusions, from either fibrin clots or omental encapsulations, are promoted by CPII and diabetes duration and insulin instability (2,3). Pathological analysis of encapsulation tissues disclosed, among predominant collagen fibrosis, inflammatory reactions, including lymphocytes and amyloid-like deposits reacting to anti-insulin antibodies, surrounded by histiocytes or giant cells (2). However, catheter obstructions were not related to high plasma anti-insulin antibody levels (4,5). Enhanced migration toward insulin and the chemotactic peptide formyl-methionyl-leucyl-phenylalanine of monocyte-issued macrophages from three patients with previous catheter encapsulations suggested that higher macrophage chemotaxis might promote these events (5). We report two unique observations of …

Complications at implantation site of implantable insulin pumps may lead to premature removal. To elucidate the origins and the outcomes of these local adverse events.We investigated seromas of the 'pump-pocket' that have been detected for an eight month-period during the follow-up of such-treated forty type 1 diabetic patients. At the start of study period, skin bacterial flora was sampled at umbilicus and groin, and isolated strains of Staphylococcus epidermidis were preserved in specific vials at -20 degreesC. Each time a seroma was detected at transcutaneous 45 days-refill of pump reservoir, it was sampled for bacterial cultures. Isolated strains of S. epidermidis from seroma were genetically compared to preserved strains of corresponding patients using Pulsed-Field Gel Electrophoresis (PFGE) after genomic restriction by SmaI.Among the ten seromas that occurred after a mean time of 9.9 months since implantation, S. epidermidis were isolated in five cases. Genetic comparison of isolated strains could be performed in three cases. Compared strains showed identical (in 2 cases) or closely related (in one case) PFGE profiles. While the five aseptic seromas resolved with rest, four infected cases required explantations after one to nineteen months in spite of antibiotic therapy and the fifth one persisted without impairment under long-term antibiotics.Our results suggest that seeding from the skin flora is a key-factor determining the severity of pump-pocket complications. We recommend that bacterial investigations of pump-pocket seromas should be systematically performed, while prophylactic measures might include antibiotic cover for each puncture of the pump-pocket.

OBJECTIVE To survey catheter complications and to analyze catheter survival during long-term intraperitoneal and intravenous insulin therapy with an implanted programmable pump with a sideport. RESEARCH DESIGN AND METHODS Catheter occlusions were documented by measuring dynamic catheter resistance. Catheter migrations or breaks were demonstrated by × ray. When flushing the catheter with buffer solution through the sideport failed to clear the occlusion, catheters were replaced or laparoscopy was performed for the excision of fibrous tissue growth. Broken or migrated catheters were replaced. RESULTS Occlusions were the most common catheter complications, and the majority of them (79% intraperitoneal and 84% intravenous) were cleared by flushing the catheter. Survival at 3 years was significantly higher for intraperitoneal catheters compared with intravenous catheters (60% intraperitoneal and 22% intravenous). CONCLUSIONS Nonsurgical management of catheter occlusions contributed to extend catheter lifetime. Intraperitoneal catheters have a lower morbidity and a higher survival than intravenous catheters.

To evaluate the efficacy on blood glucose control of long-term peritoneal insulin infusion and its consequences on the evolution of diabetic retinopathy, we analyzed retrospectively the values of glycosylated haemoglobin measured quarterly and the retinal angiograms obtained after 1, 5 and 9 years from seventeen insulin-dependent diabetic patients treated by this technique during 9.0 +/- 2.2 years. Blood glucose control was significantly improved from the first year of treatment (p < 0.01). Seventy-one per cent of patients had a level of glycosylated hemoglobin below one standard deviation of normal values after five years and ninety-two per cent of 12 patients treated up to nine years remained in the same near-normal range. Glycaemic excursions below 0.5 g/l and over 2 g/l were limited to 5-7% and 15-17% of four times-daily capillary glucose measurements respectively, along the whole IP insulin infusion period. Among 7 patients with no retinopathy (n = 1) or with mild to moderate nonproliferative retinopathy, requiring no specific ophthalmological treatment, (levels 20 to 40 on worse eye according to a simplified version of ETDRS classification, n = 6), 3 remained stable, 2 improved and 2 impaired although remaining under level 50 of the classification, after 5 to 9 years. Nine patients with severe nonproliferative (level 50, n = 1) or proliferative (level 65, n = 8) retinopathy, all treated by panretinal photocoagulation before initiation of IP treatment, improved and one patient with severe nonproliferative retinopathy, incompletely treated by laser photocoagulation, remained stable, after 5 to 9 years. No macular edematous reaction or impairment of existing macular edema occurred after panretinal photocoagulation under IP treatment. These data indicate that a sustained near-normal blood glucose control can be achieved under long-term peritoneal insulin infusion, without significant impairment of diabetic retinopathy when an initial ophthalmological evaluation, and a specific treatment if necessary, are performed.

OBJECTIVE To evaluate the incidence and investigate determinants of insulin underdelivery events occurring with implanted pumps using peritoneal route from a 103 patient-year experiment. RESEARCH DESIGN AND METHODS Of the MiniMed (MIP 2001) pumps implanted in 47 type I diabetic patients, 70 were refilled quarterly with four successive batches (A, B, C, D) of U400 Hoechst 21 PH neutral insulin during a 3-year study period. Any reduction of insulin flow rate >15% was considered as abnormal insulin delivery. Diagnosis of the cause of underdelivery was established according to the response to the following steps: 1) 0.01 mol/l NaOH rinse of pump circuits to solubilize insulin aggregates, 2) surgical examination and replacement of blocked catheters, and 3) postsurgical 0.01 mol/l NaOH rinse of pump. Step 2 was selected first if the increase of insulin requirements or reduction of flow rate were > 50%. Relative contributions of insulin and the implanted system to underdelivery events were analyzed. RESULTS There were 76 episodes of insulin underdelivery that occurred during the study, resulting in an incidence of 74 events per 100 patient-years. Of 52 NaOH pump rinses, 30 restored normal flow rate. Surgery, performed after rinse failure (n = 22) or as the first step (n = 24), disclosed catheter blockages due to tip obstructions in 28 cases and omental encapsulations in 18 other cases. Five combined severe reductions of pump flow rate requiring pump replacements were diagnosed during surgery, and additional NaOH rinses had to be performed after catheter change in 12 other cases. Analysis of the incidence of underdelivery events indicated that both pump- and catheter-related problems were significantly increased while implanted systems infused batches B, C, and D versus batch A (P < 0.01), whereas the duration of pump implantation had no significant influence. CONCLUSIONS Underdelivery events constitute serious limiting obstacles to prolonged peritoneal insulin infusion from implanted pumps. Progress in insulin pump compatibility is expected to reduce their occurrence and, thus, to improve the feasibility of this treatment.

OBJECTIVE To evaluate catheter survival and identify mechanisms involved in catheter obstructions during a 109.8 patient-year experience with implanted pumps for peritoneal insulin delivery. RESEARCH DESIGN AND METHODS Fifty-one type I diabetic patients were recruited in feasibility studies of two models of implanted systems for peritoneal insulin delivery. Both systems had a silicone–coated polyethylene catheter and infused Hoechst 21 PH neutral insulin (U400 or U100). Catheter obstruction was suspected each time the increase of insulin flow rate over 50% of usual need was insufficient to correct an impairment of glycemie control in the absence of intercurrent factors. A laparoscopie examination was then systematically performed under general anesthesia. The disclosed material occluding the catheter was submitted to a pathological analysis. By actuarial analysis, we examined the estimated effects of the potential determinants of the catheters' durations of proper operation on catheter survival. RESULTS Over an implantation duration of 25.8 ± 14.0 months (mean ± SD), 34 catheter obstructions were diagnosed in 24 patients, resulting in an incidence of 31 events per 100 patient–years. Fifty percent survival rate of the first implanted catheter was 27 months (95% confidence interval [CI]: 19–32) on actuarial analysis. Six catheters were cleared under laparos–copy and 24 were replaced, while 2 systems were definitively explan ted and 2 combined replacements of pump and catheter were performed because of an associated pump slowdown. In five cases, an alkaline rinse procedure of the pump was necessary after catheter replacement to restore usual insulin needs, suggesting an associated insulin aggregation in the pump. Twenty obstructions were due to a fibrin clot at the catheter tip, and 14 obstructions were created by a tissue encapsulation around the catheter. A previous experience of peritoneal insulin infusion from portable pumps or a longer duration of diabetes (>21 years) both appeared as conditions significantly reducing the time of a catheter's proper operation (P < 0.01 and P < 0.05, respectively) either by tip obstructions or by encapsulations. Pathological analysis of catheter encapsulations showed a collagen fibrosis in all studied patients (n = 11), which was associated with a lymphocytic infiltrate in five patients and also with anti-insulin immunoreactive amyloid deposits in four patients. Catheter tip clots were composed of fibrinlike material, nonreactive to anti-insulin antibodies. CONCLUSIONS Catheter obstruction is a frequent adverse technical event occurring with implanted insulin pumps. Progress is expected in the biocompatibility of catheter material

OBJECTIVE- To increase awareness of adverse events associated with the use of programmable implantable pumps (PIPs).CASES- There were 7 cases of complications associated with the pump-pocket among 40 patients treated by PIP, and we searched for risk factors.RESULTS- Seven of 40 type I diabetic patients treated by PIP presented severe complications of the pump-pocket, resulting in five definitive explantations and nine other surgical interventions. The lesions included an exudative reaction in the pump-pocket and a skin retraction or atrophy, which were complicated by skin erosion in five patients. Coagulase-negative staphylococcus was identified in the pump-pocket in four patients, including three cases of skin erosion. No specific risk of local complications could be attributed to age, sex, duration of diabetes, body mass index, presence of retinopathy or peripheral neuropathy, HbA(1c) level since implantation, depth of implantation in the abdominal wall, or duration of experience with PIP. Usual physical activity corresponding to >2,000 kcal energy expenditure per week, estimated by a questionnaire, appeared to be the only identified significant risk factor.CONCLUSIONS- From these results, we suggest that physical activity should be limited to moderate exercise and exclude vigorous efforts in diabetic patients treated by PIP to avoid an increased risk of complications at the implantation site.

The feasibility of the continuous intraperitoneal insulin infusion from implantable programmable systems was evaluated in 17 Type 1 (insulin-dependent) diabetic patients currently treated by external pumps. Eight subjects were using a continuous subcutaneous insulin infusion (cumulated experience: 7.4 patients x years) and nine subjects had a cumulated experience of 61.4 patients x years of continuous intra peritoneal insulin delivery by external pumps. The two studied implantable systems (A and B) were delivering the same pH neutral surfactant-stabilized semi-synthetic human insulin, but at the respective concentrations of 400 units per ml in group A (n = 12) and of 100 units per ml in group B (n = 5), via a peritoneal catheter. The pump was implanted in a subcutaneous pocket created in the abdominal wall under general anesthesia. The reported trial of implantable programmable systems is 21 patient x years with an individual experience of 1.2 +/- 0.4 years (mean +/- SD). A sustained and stable glycaemic control was obtained, as indicated by the haemoglobin A1c: 7.4 +/- 1.3% (normal range: 4.3-6.1%), the mean blood glucose: 7.4 +/- 2.1 mM.l-1, the standard deviation of blood glucose values: 3.4 +/- 0.4 mM.l-1 and the percentages of 13.1 +/- 4.5% and 6.1 +/- 6.1% of blood glucose values respectively over 11 mM.l-1 and under 2.8 mM.l-1 after one year. The only metabolic event to occur was one episode of ketoacidosis secondary to a catheter obstruction. No hypoglycaemic coma occurred contrasting with incidences of 0.54 and 0.05 per patient x year during subcutaneous external and intraperitoneal pumps respectively (p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)